JP2012097070A - Method for producing external preparation, and external preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an external preparation which can exhibit therapeutic efficacy, scarcely peels off from various areas of the body because of having high stretchability and so fitting ability, can provide a large area for the percutaneous absorption of active ingredients, can reduce the tendency of the constituent pressure-sensitive adhesive to chemically irritate a lesion, and can reduce the tendency to irritate the skin due to e.g., stuffiness because of its ability to enhance air permeability, and to provide a method for producing the same.SOLUTION: The method for producing the external preparation comprises the injection step of dissolving a pharmaceutically effective chemical ingredient in any one medium selected from among a supercritical fluid, a subcritical fluid, and liquid water of a temperature above 100°C and bringing the medium in which the chemical ingredient is dissolved into contact with a carrier to inject the chemical ingredient together with the medium into the carrier.

Description

  The present invention relates to a method for producing an external preparation such as a transdermally absorbable preparation and the external preparation produced by the method.

  The so-called poultice or patch is used for osteoarthritis, shoulder periarthritis, humeral epicondylitis (tennis elbow, etc.), tendon / tenosynovitis, peritonitis, muscle pain, swelling after trauma Widely used in the treatment of pain and the like.

  However, these poultices have the problem of poor breathability and skin irritation due to stuffiness due to the property of releasing active ingredients in close contact with the skin. In addition, adhesives are used in patches such as poultices so that the patches do not fall off the skin. However, adhesives may cause chemical skin irritation to the affected area, and patches with less irritation are desired. It was rare. In addition, poultices are difficult to stretch and contract due to the limitation of retaining the drug in the plaster, and as a result, the patch fixed by the adhesive is dropped due to intense exercise or the like. there were.

  Regarding these problems, as a poultice with good breathability, the plaster is obtained by applying a paste in the form of a mesh or a pattern composed of meshes with a gap in the rotary screen printing method, and has excellent breathability. A patch is disclosed (Patent Document 1). Further, in a patch comprising a support, a plaster applied to the support, and a film bonded to the plaster surface, a plurality of linear cuts are formed in the longitudinal direction and the lateral direction, and a breathable patch An agent or the like has been proposed (Patent Document 2).

About removal, it is a water-containing tape, and by reducing the thickness to 100 to 800 μm, the skin irritation is reduced, and the skin-containing external patch that has difficulty in removal (Patent Document 3) A new type of poultice with an adhesive tape in which an adhesive tape for preventing dropping is provided on the poultice (Patent Document 4) has been proposed.
However, these patches also lacked breathability when the skin adhesion site was viewed locally, and there was chemical skin irritation due to the adhesive. Also, it was difficult to say that it was possible to completely prevent the dropout.

JP 2001-057991 A JP 2005-154394 A Japanese Patent No. 2887548 Japanese Patent No. 4344429

  In view of the above situation, the present invention is capable of exerting a therapeutically effective medicinal effect, is rich in elasticity, fits to each part of the body and does not easily fall off, and further increases the percutaneous absorption area of the active ingredient. It is an object of the present invention to provide an external preparation that can reduce chemical irritation to an affected area due to an adhesive and can reduce breathing irritation, and can reduce skin irritation caused by stuffiness. .

  The present inventors have intensively studied in view of the above problems, and dissolve a pharmaceutically effective chemical component (hereinafter sometimes simply referred to as “drug”) in a supercritical fluid. By contacting the carrier, the drug can be injected into the carrier together with the supercritical fluid, and the carrier injected with the drug produced by such a method is therapeutically used as an external preparation such as a percutaneous absorption preparation. It has been found that it exhibits a sufficient medicinal effect. When such a production method is used, since the carrier itself into which the drug (active ingredient) is injected can be used as an external preparation, an external preparation suitable for various uses can be produced by appropriately selecting the carrier. it can. For example, when a continuous space is provided in the carrier, an external preparation with good air permeability can be produced, and therefore skin irritation such as stuffiness can be reduced. In particular, when the carrier is formed of fibers, it is an external preparation with extremely good air permeability. For example, when a film having no or low air permeability is used as a carrier, an external preparation having no or low air permeability can be obtained, and therefore, it can be suitably used for sealing therapy (also referred to as ODT therapy or sealing bandage method). In addition, according to such a production method, the carrier itself such as fiber can be used as it is as an external preparation, so that the external preparation is rich in stretchability (not limited to the stretchability of the plaster like conventional poultices). Can be manufactured. In addition, if the carrier is shaped like a cylinder to fit each part of the body, or if it is shaped like a glove, sock, etc., there is no worry of dropping off, and the carrier injected with the drug is dressed, When used for various clothes as dough, the contact area between the active ingredient and the skin (that is, the percutaneous absorption area) can be greatly increased compared to poultices. In addition, since no adhesive is used at the site of percutaneous absorption or contact with the active ingredient, skin irritation to the affected area can be reduced as compared with existing patches. The present inventors have further studied and completed the present invention.

That is, the present invention relates to the following (1) to (12).
(1) A pharmaceutically effective chemical component is dissolved in a medium selected from either a supercritical fluid, a subcritical fluid, or water in a liquid state whose temperature exceeds 100 ° C., and the chemical component is dissolved. A method for producing an external preparation, comprising an injection step of injecting the chemical component together with the medium into the carrier by bringing the medium into contact with the carrier.
(2) In the above (1), the supercritical fluid or subcritical fluid is at least one selected from the group consisting of carbon dioxide, water, methane, ethane, propane, ethylene, propylene, methanol, ethanol, and acetone. The manufacturing method as described.
(3) The production method according to the above (1) or (2), wherein the supercritical fluid or subcritical fluid is a fluid consisting essentially of carbon dioxide.
(4) The pharmaceutically effective chemical component is at least one selected from the group consisting of non-steroidal anti-inflammatory drugs, antihistamines, local anesthetics, steroids, and antiallergic agents (1) The manufacturing method in any one of-(3).
(5) The non-steroidal anti-inflammatory drug is selected from the group consisting of indomethacin or a salt thereof, felbinac, diclofenac or a salt thereof, loxoprofen or a salt thereof, ketoprofen or a salt thereof, flurbiprofen or a salt thereof, piroxicam, and meloxicam At least one selected from the group consisting of diphenhydramine or a salt thereof, chlorpheniramine or a salt thereof, promethazine or a salt thereof, hydroxyzine or a salt thereof, and dimenhydrinate The local anesthetic is at least one selected from the group consisting of lidocaine or a salt thereof, dibucaine or a salt thereof, procaine or a salt thereof, and mepivacaine or a salt thereof; a steroid agent is dexamethasone or a salt thereof; Prednisolone The at least one selected from the group consisting of methasone, triamcinolone acetonide, and triamcinolone; and the antiallergic agent is at least one selected from the group consisting of diphenhydramine or a salt thereof, and promethazine or a salt thereof ( The manufacturing method as described in 4).
(6) The production method according to any one of (1) to (5), wherein the carrier is formed from a material having air permeability.
(7) The production method according to any one of (1) to (6), wherein the carrier is formed from a fibrous substance.
(8) The production method according to any one of (1) to (7), wherein the carrier is a woven fabric or a nonwoven fabric formed from a fibrous material.
(9) The fibrous material is rayon, cupra, acetate fiber, promix, nylon, polyester fiber, acrylic fiber, polyvinyl alcohol fiber, polypropylene fiber, polyethylene fiber, polyurethane fiber, polylactic acid fiber, cotton, hemp, wool, beast The production method according to the above (7) or (8), which is at least one fiber selected from the group consisting of hair and silk.
(10) The production method according to any one of (1) to (9), wherein the carrier has a cylindrical shape, a glove shape, or a sock shape.
(11) The production method according to (3), wherein the injection step is performed under conditions of a temperature of 100 ° C. or lower and a pressure of 10 to 25 MPa.
(12) An external preparation produced by the production method according to any one of (1) to (11).

  According to the present invention, a therapeutically effective medicinal effect can be exerted, and since it is rich in elasticity, it is excellent in feeling of use, fits to each part of the body and hardly falls off, and further, percutaneous absorption area or skin of the active ingredient Since the contact area can be increased, it can be applied to any part of the body, and the chemical irritation to the affected area by the adhesive can be reduced. The external preparation which can be reduced can be manufactured. The external preparation manufactured by such a method is suitably used for treatment of inflammation or pain, wound treatment, pressure ulcer treatment, and the like.

FIG. 1 is a diagram showing an example of a method of using one aspect of the external preparation of the present invention. FIG. 2 is a diagram showing the amount of indomethacin injected into the polyethylene terephthalate nonwoven fabric by supercritical carbon dioxide under each temperature and pressure. FIG. 3 is a diagram showing the amount of felbinac injected into the polyethylene terephthalate nonwoven fabric by supercritical carbon dioxide under each temperature and pressure. FIG. 4 is a diagram showing the amount of diclofenac injected into the polyethylene terephthalate nonwoven fabric by supercritical carbon dioxide under each temperature and pressure. FIG. 5 is a diagram illustrating an example of a result of a carrageenin-induced foot edema suppression test. FIG. 6 is a diagram illustrating an example of a result of a carrageenin-induced foot edema suppression test. FIG. 7 is a diagram illustrating an example of a result of a carrageenin-induced foot edema suppression test. FIG. 8 is a graph showing an example of the results of a pharmacological test using a compound 48 / 80-induced mouse pruritus model. FIG. 9 is a diagram illustrating an example of a result of a carrageenin-induced foot edema suppression test. FIG. 10 is a photograph for explaining a pain response by administration of formalin. FIG. 11 is a diagram showing an example of the results of a pharmacological test using a formalin-induced mouse pain model.

In the method for producing an external preparation of the present invention, a pharmaceutically effective chemical component (drug) is selected from a supercritical fluid, a subcritical fluid, or water having a temperature exceeding 100 ° C. And injecting the chemical component into the carrier together with the medium by bringing the medium in which the chemical component is dissolved into contact with the carrier.
The injection of a chemical component (drug) into a carrier means that the drug is supported, held, or supported inside or on the surface of the carrier.
As long as the effects of the present invention are exhibited, the method of the present invention includes a step of cutting or molding the carrier into a desired size or shape, a step of drying the carrier, a step of bonding the carrier, etc. May be included. The step of cutting or molding the carrier into a desired size or shape, the step of drying the carrier, and the like may be performed before or after the drug injection. The step of drying the carrier is preferably performed after drug injection.

  The method for producing an external preparation of the present invention is suitable, for example, as a method for producing an external skin preparation. In particular, it is suitable as a method for producing a transdermally absorbable preparation.

  The pharmaceutically effective chemical components are preferably those usually used for external preparations, and may be appropriately selected depending on the application. For example, those having transdermal absorbability are more preferred. Among them, a drug used for the treatment of inflammatory diseases, bruises, sprains, back pain, wounds, pressure sores, pain, pruritus and the like is preferable. As such a drug, for example, at least one selected from the group consisting of a nonsteroidal anti-inflammatory drug (NASID), an antihistamine, a local anesthetic, a steroid, and an antiallergic agent is preferable. Only one type of drug may be used, or two or more types may be used in combination. Among these, as the drug in the present invention, non-steroidal anti-inflammatory drugs, local anesthetics, steroid drugs, anti-allergic drugs and the like are preferable, and non-steroidal anti-inflammatory drugs, steroid drugs, anti-allergic drugs and the like are more preferable.

  Non-steroidal anti-inflammatory drugs are drugs that do not have a steroid skeleton and exhibit anti-inflammatory effects. As the non-steroidal anti-inflammatory drug, indomethacin or a salt thereof, felbinac, diclofenac or a salt thereof, loxoprofen or a salt thereof, ketoprofen or a salt thereof, flurbiprofen or a salt thereof, piroxicam, meloxicam and the like are preferable. Among them, indomethacin or a salt thereof, felbinac, diclofenac or a salt thereof is more preferable. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt.

  As the antihistamine, diphenhydramine or a salt thereof, chlorpheniramine or a salt thereof, promethazine or a salt thereof, hydroxyzine or a salt thereof, dimenhydrinate and the like are preferable. Of these, diphenhydramine or a salt thereof, chlorpheniramine or a salt thereof, promethazine or a salt thereof, and the like are more preferable. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt.

  The local anesthetic is preferably lidocaine or a salt thereof, dibucaine or a salt thereof, procaine or a salt thereof, mepivacaine or a salt thereof, and the like. Of these, lidocaine or a salt thereof, dibucaine or a salt thereof, procaine or a salt thereof, and the like are more preferable. More preferred is dibucaine or a salt thereof, procaine or a salt thereof, and the like. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt.

  The steroid is preferably prednisolone and derivatives thereof, dexamethasone and derivatives thereof, betamethasone and derivatives thereof, triamcinolone and derivatives thereof, hydrocortisone and derivatives thereof, and more specifically, dexamethasone or a salt thereof, prednisolone, betamethasone, triamcinolone and derivatives thereof. The derivative, estradiol, is preferred. As the derivative of triamcinolone, triamcinolone acetonide, triamcinolone diacetate and the like are preferable. Of these, dexamethasone or a salt thereof, triamcinolone, triamcinolone acetonide and the like are more preferable. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt.

  As the antiallergic agent, diphenhydramine or a salt thereof, promethazine or a salt thereof, and the like are preferable. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt.

A supercritical fluid is a state of a substance at a temperature and pressure above the critical point. When the temperature and pressure are both above the critical point, the substance assumes a special state that is different from a liquid or a gas. A critical point is a point on the phase diagram that indicates the limits of temperature and pressure ranges where a phase transition between a gas phase and a liquid phase of a substance can occur.
In view of the characteristics of the present invention, a supercritical fluid is used as a medium even when a subcritical fluid according to a supercritical fluid or a liquid in which the temperature exceeds 100 ° C. is used as a medium for injecting a drug into a carrier. It is easily predicted that the same effect as the case can be obtained.
In the present invention, either a supercritical fluid, a subcritical fluid, or liquid water whose temperature exceeds 100 ° C. can be used as a medium for injecting the drug into the carrier. Use fluid.

  The supercritical fluid and subcritical fluid in the present invention are preferably carbon dioxide, water, methane, ethane, propane, ethylene, propylene, methanol, ethanol, acetone and the like. The supercritical fluid and the subcritical fluid may be composed of only one of them, or may be a mixture of two or more. Especially, since it is easy to dry after the injection treatment, a gas that is a gas at normal temperature, such as carbon dioxide, is preferable. Particularly preferably, the supercritical fluid is a fluid consisting essentially of carbon dioxide. The supercritical fluid of carbon dioxide (supercritical carbon dioxide) is nonflammable, is a gas at room temperature, and is easy to dry after injection treatment, is inexpensive, and has a relatively low critical point temperature and pressure ( The critical point of carbon dioxide: 31.1 ° C., 7.4 MPa) is preferable because it has advantages such as low reactivity with the carrier to be injected (carrier to which the drug is injected).

The carrier in the present invention is an object that can support, hold, or carry a pharmaceutically effective chemical component inside or on the surface thereof.
The carrier in the present invention is not particularly limited and can be appropriately selected depending on the purpose. For example, a film-like substance, a fibrous substance, a woven fabric formed from a fibrous substance, a non-woven fabric, and the like can be given. Two or more kinds of carriers may be used in appropriate combination.

  Examples of the film-like substance include rayon, cupra, acetyl cellulose, promix, nylon, polyester, acrylic, polyvinyl alcohol, polypropylene, polyethylene, polyurethane, polylactic acid, or a film made of fibroin. Of these, films of nylon, polyester, polypropylene, polyethylene and the like are preferable. For example, an external preparation using a film of nylon, polyester, polypropylene, polyethylene or the like that has no or low air permeability as a carrier is suitable for sealing therapy and the like.

In the present invention, the carrier is preferably formed from a material having air permeability. As a material having air permeability, for example, a fibrous material is suitable. That is, the carrier in the present invention is preferably formed from a fibrous material.
The degree of air permeability is not particularly limited as long as it can permeate moisture transpirated from the skin at the time of use, but it is usually measured by the air permeability measurement (Fragile method) of the JIS L-1096 general fabric test method. The measured value is 0.1 cc / cm ² / sec or more, preferably 1 cc / cm ² / sec or more, more preferably 10 cc / cm ² / sec or more.
Moreover, it is advantageous from the viewpoint of the size of the drug release area that the carrier is fibrous.

  The fibrous material is preferably flexible and cohesive, and for example, fibers are preferably used. The fiber may be either a chemical fiber or a natural fiber. Examples of the chemical fiber include rayon, cupra, acetate fiber, promix, nylon, polyester fiber, acrylic fiber, polyvinyl alcohol fiber (acetalized polyvinyl alcohol), polypropylene fiber, polyethylene fiber, polyurethane fiber, and polylactic acid fiber. Examples of natural fibers include cotton, hemp (ramie, linen, etc.), wool (wool), animal hair (mohair, cashmere, camel, etc.), silk (silk), and the like. These may be used alone or in combination of two or more. Among these, chemical fibers are preferable, nylon, polyester fibers, polyvinyl alcohol fibers, polypropylene fibers, polyethylene fibers, polyurethane fibers, and the like are more preferable, nylon, polyester fibers, polypropylene fibers, polyethylene fibers, and the like are further preferable, and polyester fibers are particularly preferable. Polyester is a polycondensate of polycarboxylic acid (dicarboxylic acid) and polyalcohol (diol). Among these, polyethylene terephthalate (PET) fibers are preferably used from the viewpoints of chemical resistance, strength, price, and the like.

  As the carrier in the present invention, a woven fabric or a nonwoven fabric formed from a fibrous substance is suitable. The non-woven fabric is arranged in a web-like (thin cotton) or mat-like manner by an appropriate method without weaving or knitting the fibers, and then bonding the fibers together by an adhesive, heat treatment, or frictional force between the fibers. It is made into a sheet by weaving. As the nonwoven fabric in the present invention, needle punch nonwoven fabric, water jet punch (spun lace, hydroentangled) nonwoven fabric, melt blown nonwoven fabric, spunbond nonwoven fabric, stitch bond nonwoven fabric, thermal bond nonwoven fabric, chemical bond nonwoven fabric, wet nonwoven fabric, etc. are suitably used. . Of these, needle punched nonwoven fabrics, water-jet punched (water flow entangled) nonwoven fabrics and the like are preferable.

  The size and shape of the carrier are not particularly limited and can be appropriately selected according to the size of the affected area. For example, a sheet form, a ribbon form, etc. are mentioned. Moreover, in this invention, it is preferable that the support | carrier is formed in the shape which fits each part of a body. This makes it difficult for the transdermal absorbent to fall off each part of the body. As such a carrier, for example, a cylindrical shape, a glove shape, or a sock shape is suitable. For example, a woven fabric or a non-woven fabric formed in such a shape is one of the preferred embodiments of the carrier in the present invention. In the case of a cylindrical shape or the like, an opening may be provided in part for bending the joint.

  In the injection step, there is no particular limitation on the method in which the drug is dissolved in a supercritical fluid, subcritical fluid, which is a medium, or water in a liquid state whose temperature exceeds 100 ° C., and the medium in which the drug is dissolved is brought into contact with the carrier. For example, if the medium is a supercritical fluid, the drug, the carrier, and the fluid (supercritical fluid) may be allowed to coexist at a temperature and pressure that are at or above the critical point of the fluid to be used. For example, a supercritical fluid will be described as an example. Usually, a drug and a carrier are placed in a pressure-resistant reaction vessel such as a pressure-resistant reaction tube, and the fluid is put into a supercritical state by injecting the fluid while being pressurized. The injection process can be performed by maintaining the fluid at a predetermined temperature. Also, as a device having a pressure-resistant reaction vessel such as a pressure-resistant reaction tube, a supercritical fluid extraction device (for example, ISCO, model number SFE System 2200, JASCO, model number SCF-Sro) can be suitably used. For example, by placing a drug and a carrier in a supercritical fluid extraction device, raising the temperature and pressure in the device to a predetermined range, and then introducing a fluid into the device to maintain the device at a predetermined temperature and pressure. The drug can be dissolved in the supercritical fluid, and the supercritical fluid in which the drug is dissolved can be brought into contact with the carrier. When the supercritical fluid in which the drug is dissolved comes into contact with the carrier, the drug is injected into the carrier together with the supercritical fluid.

  The temperature and pressure in the injection step may be appropriately selected according to the type of medium used, but it is preferable to select a temperature and pressure range in which the carrier and the drug are stable. For example, when carbon dioxide, which is a supercritical fluid (preferably a fluid consisting essentially of carbon dioxide) is used as the medium, the temperature of the injection process is preferably about 120 ° C. or less, more preferably about 100 ° C. or less. It is. The lower limit of the temperature of the injection process is preferably about 40 ° C. The temperature of the injection process is more preferably about 40 to 100 ° C. The pressure is preferably about 5 to 25 MPa, more preferably about 10 to 25 MPa, more preferably about 15 to 25 MPa, and particularly preferably about 20 to 25 MPa. That is, it is preferable to coexist a drug, a carrier and carbon dioxide under such temperature and pressure conditions, dissolve the drug in carbon dioxide, and contact the carbon dioxide in which the drug is dissolved with the carrier.

  For example, when the drug is a non-steroidal agent and carbon dioxide is used as the supercritical fluid or subcritical fluid, a particularly preferred injection condition in the injection process is a temperature of about 60-100 ° C, more preferably about 80-100 ° C. It is. The pressure is preferably about 10 to 25 MPa, more preferably about 15 to 25 MPa, and particularly preferably about 20 to 25 MPa. When the drug is a non-steroidal agent and carbon dioxide is used as the supercritical fluid or subcritical fluid, the temperature is about 60 to 100 ° C., the pressure is preferably about 10 to 25 MPa, and the temperature is about 80 to 100 ° C. Yes, more preferably a pressure of about 15-25 MPa.

  For example, when the drug is a steroid or antiallergic agent and carbon dioxide is used as the supercritical fluid or subcritical fluid, the preferred temperature in the injection step is about 40-120 ° C., more preferably about 40- The temperature is 100 ° C, more preferably about 40 to 80 ° C. When the drug is a steroid or antiallergic agent and carbon dioxide is used as the supercritical fluid or subcritical fluid, the conditions in the injection step are as follows: the temperature is about 40 to 120 ° C. (more preferably about 40 to 100 ° C. The pressure is preferably about 5 to 25 MPa, the temperature is about 40 to 80 ° C., and the pressure is about 5 to 20 MPa.

  For example, when the drug is a local anesthetic and carbon dioxide is used as the supercritical or subcritical fluid, a particularly preferred infusion condition in the infusion process is a temperature of about 40-80 ° C, more preferably about 40-60 ° C. It is. The pressure is preferably about 10 to 25 MPa, more preferably about 10 to 20 MPa, and particularly preferably about 10 to 15 MPa. When the drug is a local anesthetic and carbon dioxide is used as the supercritical fluid or subcritical fluid, the temperature is about 40 to 80 ° C., the pressure is preferably about 10 to 25 MPa, and the temperature is about 40 to 60 ° C. Yes, more preferably a pressure of about 10 to 15 MPa.

  For example, when injecting into a polyester nonwoven fabric using carbon dioxide as a supercritical fluid or subcritical fluid as a medium, it should be performed under conditions of a temperature of about 40 to 120 ° C. and a pressure of 5 to 25 MPa. It is more preferable that the reaction is carried out under conditions of a temperature of 60 to 120 ° C. and a pressure of 10 to 25 MPa. The temperature is more preferably about 60-100 ° C. When carbon dioxide is used as the supercritical fluid, a more preferable injection condition in the injection step is a temperature of about 80 to 100 ° C. The pressure is more preferably about 15 to 25 MPa, and further preferably about 20 to 25 MPa.

  When liquid water having a temperature exceeding 100 ° C. is used as the medium in the injecting step, the temperature of the water is preferably, for example, a temperature exceeding about 100 ° C. to 150 ° C., and more preferably 110 ° C. to 130 ° C. The pressure in the injection process is preferably about 0.1 MPa.

  The time for performing the injection step is not particularly limited, but is preferably about 0.25 to 2 hours, and more preferably about 30 minutes to 1 hour. It is preferable that the time of the injection process be in such a range because a sufficient injection amount can be obtained without applying a load to the carrier.

  The amount of the drug used in the injection step is usually preferably about 0.1 to 50% by mass, more preferably about 0.3 to 20% by mass with respect to the carrier mass. Such a range is preferable because a sufficient injection amount can be obtained and a drug loss can be suppressed to a small extent.

  In the injection step, components other than the drug and medium (supercritical fluid, subcritical fluid, or water in a liquid state having a temperature exceeding 100 ° C.) may be injected into the carrier as desired. Such a component may be any component that is pharmaceutically acceptable, and examples thereof include a transdermal absorption enhancer, a fragrance, and a pigment. When injecting other components together with the drug into the carrier, in the injection process, the drug, other components, the carrier and the medium are allowed to coexist, the drug and other components are dissolved in the medium, and the medium is brought into contact with the carrier. You can do it.

After performing the injection step, it is preferable not to clean the surface of the resulting carrier.
The medium (supercritical fluid, subcritical fluid or liquid water whose temperature exceeds 100 ° C.) injected into the carrier together with the drug in the injection step is, for example, when a gaseous fluid at normal temperature such as carbon dioxide is used. Is released from the carrier and removed by placing the carrier at room temperature.

In the present invention, if necessary, a step of drying the carrier into which the drug has been injected by the above step can be performed. By performing the drying step, the supercritical fluid, subcritical fluid, or water used as the medium can be efficiently removed, and the residue of the components used as the medium can be minimized. The drying is usually performed at about 0 to 40 ° C, preferably about 10 to 20 ° C. The drying time is usually about 0.5 to 4 hours, preferably about 1 to 3 hours. Although depending on the types of drug and carrier, generally, drying by heating after drug injection is not preferable because the drug flows out of the carrier. Therefore, drying is preferably performed under reduced pressure, and the pressure is usually about 10 ⁻³ mmHg or less, preferably about 10 ⁻⁴ mmHg or less, more preferably about 10 ⁻⁵ mmHg or less.

The amount of drug injected into the carrier (drug injection amount) can be measured, for example, by the following procedure.
(1) The carrier is cut into an appropriate size or formed into a desired shape. If necessary, the carrier is dried with a vacuum desiccator. The mass (W _i ) of the carrier after drying is measured.
(2) A carrier and a drug are added into a cell of a supercritical fluid extraction apparatus (for example, model number SFE System 2200 manufactured by ISCO, model number SCF-Sro manufactured by JASCO).
(3) An injection process is performed by maintaining the inside of the cell at a predetermined pressure and temperature for a predetermined time.
(4) After the injection treatment, the carrier is dried in a vacuum desiccator (about 10 ⁻⁵ mmHg) for about 1 to 3 hours. After drying, the mass (W _sc ) of the carrier after drug injection is measured. When storing the surface of the carrier without washing, it is preferable to store it at room temperature in a dark place.

The amount of drug injected into the carrier (drug injection amount), the simple, the calculation formula for W _sc -W _i, indirectly confirmed by determining the mass increase. However, depending on the combination of the carrier and the medium used, the constituent components of the carrier (for example, when the carrier is a polymer, residual monomer, plasticizer, etc.) are dissolved in the medium used in the injection process, and the mass is reduced. It is necessary to confirm in advance. A more accurate drug injection amount can be easily measured, for example, by quantifying the drug concentration in a liquid extracted with a solvent such as isopropanol by HPLC, absorbance measurement or the like.

The external preparation produced by the above production method is capable of exerting a therapeutically effective medicinal effect because the drug injected into the carrier is released when applied to the skin, and the active ingredient can be transdermally used. Absorption area or skin contact area can be increased. Further, the external preparation obtained by the above production method is excellent in feeling of use because of its excellent stretchability, and can be applied to any part of the body because it fits to each part of the body and does not easily fall off. The external preparation obtained by the above production method is also excellent in safety not to damage the stratum corneum of the skin at the time of peeling at the site where the active ingredient is percutaneously absorbed or the site where the active ingredient contacts the skin. It is excellent in usability without feeling cold.
Furthermore, in the above manufacturing method, for example, when a woven fabric, a nonwoven fabric, or the like formed from a fibrous substance is used as a carrier, the resulting external preparation has a high air permeability, so the stuffiness when applied to the skin is reduced. It has been done. Further, for example, when a film or the like with little or no breathability is used as a carrier, the resulting external preparation has no or little breathability, so that when applied to the skin, an effect of sealing therapy can be obtained.
Such external preparations produced by the above production method are also included in the present invention. The external preparation is preferably an external skin preparation, and among them, a transdermal absorption preparation is preferable.

  The shape of the external preparation of the present invention is not particularly limited, and can be any shape such as a sheet shape, a ribbon shape, a cylindrical shape, a glove shape, and a sock shape. Moreover, an external preparation can also be used as clothes, cloth, etc., various clothes, sheets, etc. The method for molding the external preparation is not particularly limited. In the above-described production method, the carrier used for the injection step may be cut or molded in a desired size or shape in advance, and after the injection step, a drug (medicine) May be cut or molded into a desired size or shape.

  The appropriate amount of the external preparation of the present invention varies depending on the active ingredient, but in general, the content of the drug as the active ingredient is about 0.01 to 10% by mass relative to the preparation (external preparation). Preferably, it is about 0.03-5 mass%. Such a range is preferable because an active ingredient necessary for treatment can be effectively administered to the affected area or the whole body. When the production method of the present invention is used, an external preparation containing the above amount of drug can be produced.

For example, when the drug used for the external preparation of the present invention is a non-steroidal agent, the content of the drug is preferably about 0.1 to 10% by mass with respect to the preparation, and about 0.3 to 3 More preferably, it is mass%.
When the drug used in the external preparation of the present invention is a steroid or antiallergic agent, the content of the drug is preferably about 0.01 to 10% by mass with respect to the preparation, More preferably, it is 03-5 mass%, and it is further more preferable that it is about 0.05-3 mass%.
For example, when the drug used for the external preparation of the present invention is a local anesthetic, the content of the drug is preferably about 0.01 to 10% by mass with respect to the preparation, and about 0.05 to 5%. It is more preferable that it is mass%, and it is further more preferable that it is about 0.1-3 mass%.
Such a range is preferable because an active ingredient necessary for treatment can be effectively administered to the affected area or the whole body.

  The external preparation of the present invention is suitably applied to the skin (preferably the affected area). Usually, the active ingredient can be administered to the affected area or the whole body by bringing the external preparation of the present invention into contact with the administration site. The method for applying the external preparation of the present invention to each part of the body is not particularly limited. For example, in the case where the carrier itself does not have adhesiveness, a part having the adhesiveness, or a part of the external preparation or The whole may be covered and fixed to the administration site, or the external preparation may be fixed by wrapping a bandage or the like or using a net bandage or the like. In the case where the carrier is a stretchable material, for example, when the external preparation is cylindrical, etc., as shown in the example of FIG. 1, it can be used like a supporter to cover the affected part or to be in contact with the affected part. In the case of a glove shape, a sock shape, etc., it can be worn like a glove or a sock to cover or contact the affected area. The external preparation can be brought into contact with the affected area in the form of a sheet or the like.

External preparations of the present invention include, for example, rheumatoid arthritis, osteoarthritis, inflammatory diseases such as postoperative and post-extraction pain, bruises, sprains, low back pain, wounds, pressure ulcers, pain, pruritus, burns, bruises, chapped, It is suitably used for prevention or treatment of coldness, ringworm, etc. Therefore, the external preparation of the present invention is suitable as a preventive or therapeutic agent for the above diseases. In particular, when non-steroidal anti-inflammatory drugs (NSAIDs) are used as active ingredients (drugs), inflammatory diseases such as rheumatoid arthritis, osteoarthritis, postoperative and post-extraction pain, bruises, sprains, and back pain Suitable for prevention or treatment of wounds, pressure ulcers, and pain. When steroids are used as the active ingredient (drug), prevention of lichenoid eczema, dermatitis, prurigo group (including fixed urticaria), psoriasis vulgaris, palmoplantar pustulosis, scar / keloid etc. Suitable for treatment. When an antiallergic agent is used as an active ingredient (drug), it is suitable for the prevention or treatment of allergic contact dermatitis, eczema, rash, urticaria and the like. When a local anesthetic is used as the active ingredient (drug), in addition to prevention or treatment of bruises, sprains, back pain, wounds, pressure sores, pain, etc., local anesthesia before surgery and various pain relief associated with shingles Suitable for the purpose.
In addition, for example, when an external preparation manufactured using a carrier that is not breathable or low is fixed to the affected area, an effect as a sealing therapy can be obtained.

  The target to which the percutaneous absorption preparation of the present invention is applied is not particularly limited, and humans, mammals other than humans (dogs, cats, monkeys, rats, mice, rabbits, cows, pigs, horses, etc.), other useful animals, etc. Is mentioned. Preferred are humans, and more preferred are patients with the above diseases.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in more detail, these do not limit this invention at all.

Test Example 1: Examination of injection conditions The drug was injected into the carrier by the following procedure.
(1) After cutting a polyethylene terephthalate (PET) non-woven fabric (manufactured by Vilene, trade name EW-9400) to 5 cm × 5 cm with a heat cutter, the cut carrier is dried with a vacuum desiccator, and its mass (W _i ) is determined. Measured with an electronic balance.
(2) Carrier and drug (Indomethacin (Yatsushiro Pharmaceutical Co., Ltd.), Felbinac (Kolon Life Science Inc.) or Diclofenac (Henan Dongtai Pharm Co.) in a cell of a supercritical fluid extraction device (ISCO, model number SFE System 2200) , Ltd.)). The drug mass was approximately 10% by mass of the carrier mass.
(3) The cell was put into the apparatus, the temperature and pressure in the cell were raised to a predetermined temperature and pressure, carbon dioxide was fed, and an injection process was performed for 30 minutes.
(4) After the injection treatment, the carrier was dried in a vacuum desiccator for 2 hours, and the mass (W _sc ) of the carrier after drug injection was measured with an electronic balance. The surface of the carrier was stored in a dark place at room temperature without washing.

Injection of drug, the equation of W _sc -W _i, was confirmed by determining the mass increase. The mass change rate (%) was obtained by a calculation formula of 100 × (W _sc −W _i ) / W _i . The drug injection amount when the temperature and pressure when injecting each drug into the polyester nonwoven fabric is changed to 60 to 120 ° C. and 10 to 25 MPa, respectively, is shown in FIGS. FIG. 2 shows the amount of drug injected into the carrier under each treatment condition when indomethacin was used as the drug. FIG. 3 shows the amount of drug injected into the carrier under each processing condition when felbinac is used as the drug. FIG. 4 shows the amount of drug injected into the carrier under each treatment condition when diclofenac is used as the drug.
In the polyester nonwoven fabric, since the embrittlement of the nonwoven fabric material was recognized under the condition of 100 ° C. or higher, it was found that the condition of less than 100 ° C. and 15 to 25 MPa was preferable.

Example 1
A polyethylene terephthalate (PET) hydroentangled nonwoven fabric (manufactured by Nippon Vilene, trade name EW-9400) was cut into 2 cm × 2 cm with a heat cutter, and then the cut carrier was dried with a vacuum desiccator. Subsequently, the support | carrier and indomethacin were put into the cell of the supercritical fluid extraction apparatus (the product made by ISCO, model number SFE System 2200). The drug mass was 10% by mass of the carrier mass. The cell was put into the apparatus, the temperature and pressure in the cell were increased to 80 ° C. and 20 MPa, carbon dioxide was fed, and the carrier was injected for 30 minutes. After the injection treatment, the carrier was dried in a vacuum desiccator for 2 hours. The rate of change in injection after injection was about 0.25%, no significant change was observed in the appearance and characteristics of the carrier, and the air permeability was extremely high. In addition, the water entangled nonwoven fabric made from a polyethylene terephthalate (PET) which does not perform the said process was used as control.

Example 2
Felbinac as a drug, polyethylene terephthalate hydroentangled nonwoven fabric as a carrier (trade name EW-9400, manufactured by Nippon Vilene Co., Ltd.), carbon dioxide as a supercritical fluid, and conditions of 80 ° C. and 25 MPa for 30 minutes. Similarly, the drug was injected into the carrier. The rate of change in injection after injection was about 1.25%, no significant change was observed in the appearance and characteristics of the carrier, and the air permeability was extremely high.

Example 3
Diclofenac as a drug, polyethylene terephthalate hydroentangled nonwoven fabric (Nippon Vilene Co., Ltd., trade name EW-9400) as a carrier, carbon dioxide as a supercritical fluid, and conditions of 80 ° C. and 20 MPa for 30 minutes. Similarly, the drug was injected into the carrier. The rate of change in injection after injection was about 1.3%, no significant changes were observed in the appearance and characteristics of the carrier, and the air permeability was extremely high.

About each formulation manufactured in Examples 1-3, the medicinal effect was evaluated with the following test method.
Carrageenin-induced paw edema suppression test animals: Rat (Wistar strain, male, 6 weeks old at delivery, manufactured by SLC Japan)
Specimen: Group I No treatment (control); Group II Commercially available patch (trade name “Vantelin Kowa Pup S”, manufactured by Kowa Co., Ltd.); Group III Indomethacin-injected non-woven fabric produced in Example 1; Group IV Example Felvinac-injected non-woven fabric produced in No. 2; Group V Diclofenac-injected non-woven fabric produced in Example 3 (n = 8 in all)
Sample size: 2cm x 2cm
Inflammator: 1% carrageenan / saline

Test procedure: The hair of the rat's legs was previously removed using a human hair removal cream on the day before the experiment day. The foot volume of the rat right hind limb was measured with a foot volume measuring device, and 0.1 mL of a 1% carrageenan solution as an inflammation agent was administered subcutaneously to the footpad of the hind limb, and then each specimen was attached.
Four hours after application, the specimen was removed and the right hind paw volume was measured.

Evaluation method: The edema rate was calculated from the foot volume before and 4 hours after administration of the inflammatory agent, using the following formula as an index of the anti-inflammatory effect.
Edema rate (%) = [(Foot volume 4 hours after administration of the inflammation agent−Foot volume before administration of the inflammation agent) / Foot volume before administration of the inflammation agent] × 100

Test Significant differences with respect to Group I (control) were determined by the Dunnett method (*: P <0.05, **: P <0.01).

Test results Test results are shown in Table 1 and Figs. The results in Table 1 and FIGS. 5-7 are expressed as mean ± standard error (SE). FIG. 5 is a comparison of Group III (indomethacin-injected nonwoven fabric of Example 1) with Group I (no treatment: control) and Group II (commercial cataplasm). FIG. 6 is a comparison of Group IV (Ferbinac-injected nonwoven fabric of Example 2) with Group I (no treatment: control) and Group II (commercial cataplasm). FIG. 7 is a comparison of Group V (diclofenac-injected nonwoven fabric of Example 3) with Group I (no treatment: control) and Group II (commercial cataplasm).

As a result of comparing the edema rate of Group I (control), Group II (commercial cataplasm), and Group III (Example 1), Group II (commercial cataplasm) and Group I (commercial cataplasm) In group III (Example 1), a significant inhibitory effect was confirmed (Dunnett, *: P <0.05, **: P <0.01).
Moreover, as a result of comparing Group II (commercial cataplasm) and Group III (Example 1), no significant difference was found (t test and Tukey-kramer).

As a result of comparing the edema rates of Group I (control), Group II (commercial cataplasm) and Group IV (Example 2), Group II (commercial cataplasm) and Group I (commercial cataplasm) In group IV (Example 2), a significant inhibitory effect was confirmed (Dunnett, *: P <0.05, **: P <0.01).
Moreover, as a result of comparing Group II (commercial cataplasm) and Group IV (Example 2), no significant difference was found (t test and Tukey-kramer).

As a result of comparing the edema rates of Group I (control), Group II (commercial cataplasm) and Group V (Example 3), Group II (commercial cataplasm) and Group I (commercial cataplasm) In group V (Example 3), a significant inhibitory effect was confirmed (Dunnett, *: P <0.05, **: P <0.01).
Moreover, as a result of comparing Group II (commercial cataplasm) and Group V (Example 3), no significant difference was found (t test and Tukey-kramer).

  When the preparations produced in Examples 1 to 3 were used, edema was significantly suppressed as compared to the untreated first group (control). Furthermore, since the preparations produced in Examples 1 to 3 were composed of a nonwoven fabric, they were extremely rich in air permeability as compared with commercially available cataplasms.

Example 4
In the following procedure, a drug (drug) was injected into a carrier (nonwoven fabric) to prepare a specimen in which the drug was injected into the nonwoven fabric. Diphenhydramine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.) was used as the drug.
(1) Polyethylene terephthalate (PET) hydroentangled nonwoven fabric (manufactured by Japan Vilene Co., Ltd., trade name EW-9400) was cut into 5 cm × 30 cm with a heat cutter, and then the cut carrier was dried with a vacuum desiccator, and its mass ( _Wi ) was measured with an electronic balance.
(2) a glass filter paper supercritical fluid extraction apparatus (JASCO Corporation, model number SCF-SRO Is) was cut to the size of the cell, was subjected to mass measurement (this mass was set to W _ii). The cell (column) volume of the used supercritical fluid extraction device (manufactured by JASCO, model number SCF-Sro) was 50 mL.
(3) A drug solution was prepared by diluting diphenhydramine hydrochloride to 50 g / L using distilled water as a solvent.
(4) The drug solution prepared in (3) is added dropwise to the glass filter paper cut in (2) in such an amount that the drug is 5% by mass (5% owf) relative to the PET water-entangled nonwoven fabric as the carrier. The mass was measured (this mass was _designated as W _iii ).
(5) In a cell of a supercritical fluid extraction device (manufactured by JASCO, model number SCF-Sro), a glass filter paper carrying a carrier (water-entangled nonwoven fabric made of PET) and a drug (diphenhydramine hydrochloride) of (4) I put it in. After putting the cell into the device and raising the temperature and pressure in the cell to 40 ° C. and 10 MPa, carbon dioxide (liquefied carbon dioxide, purity 99.5% or more, manufactured by Uno Oxygen Co., Ltd.) is fed and injected into the carrier for 30 minutes. Went. After this injection treatment, a glass filter paper carrying a carrier and a drug (diphenhydramine hydrochloride) was dried in a vacuum desiccator for 2 hours. The mass (W _sc ) of the carrier after drug injection and the mass (W _iv ) of the glass filter paper carrying the drug (diphenhydramine hydrochloride) were measured with an electronic balance. The surface of the carrier was stored in a dark place at room temperature without washing.
Samples were prepared twice by the above procedure, and samples (a) and (b) were obtained. For each specimen, no significant changes were observed in the appearance and characteristics of the carrier, and the air permeability was extremely high.

The dissolution rate and mass change rate were calculated according to the following formula.
The dissolution rate (the ratio of the reagent supported on the filter paper dissolved in supercritical carbon dioxide) was determined by the calculation formula of 100 × (W _iii -W _iv ) / (W _iii -W _ii ).
Injection of drug, the equation of W _sc -W _i, was confirmed by determining the mass increase. The mass change rate (%) (the ratio of the mass change of the treated PET nonwoven fabric) was determined by a calculation formula of 100 × (W _sc −W _i ) / W _i .
Table 2 shows the results of injecting diphenhydramine hydrochloride into the PET water-entangled nonwoven fabric.

Example 5
In the same manner as in Example 4 except that in Example 4 (5), promethazine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.) was used as the drug, and the injection treatment was performed at 60 ° C. and 10 MPa for 30 minutes. The drug (promethazine hydrochloride) was injected into the carrier. In the same manner as in Example 4, the specimen was prepared twice to obtain specimen (c) and specimen (d). For each specimen, no significant changes were observed in the appearance and characteristics of the carrier, and the air permeability was extremely high.
Table 3 shows the results of injecting promethazine hydrochloride into the PET hydroentangled nonwoven fabric.

  In the specimens (a) to (d) obtained in Examples 4 and 5, each specimen having a large mass change rate (specimen (a) for diphenhydramine hydrochloride and specimen (c) for promethazine hydrochloride) was used. Thus, in Example 6 described later, a pharmacological test using a compound 48 / 80-induced mouse pruritus model was performed.

Example 6
(Pharmacological effect test using compound 48 / 80-induced mouse pruritus model)
The sample (a) containing diphenhydramine hydrochloride prepared in Example 4 was attached to the diphenhydramine hydrochloride administration group. The sample (c) containing promethazine hydrochloride prepared in Example 5 was administered to the promethazine hydrochloride administration group.
As a control, a water entangled nonwoven fabric made of polyethylene terephthalate (PET) that was not subjected to the treatment of Examples 4 and 5 (no treatment) was used.

Experimental method model: Compound 48 / 80-induced mouse pruritus model Animal used: Mouse (ICR system, male, 5 weeks of age at delivery, purchased from Japan SLC)
Number of cases and group composition:
Group I: Control group (untreated non-woven fabric) (n = 8)
Group II: Diphenhydramine hydrochloride administration group (n = 8)
Group III: Promethazine hydrochloride administration group (n = 7)
Group IV: Positive control group (Muhi (registered trademark) Patch A, manufactured by Ikeda Model Hall) (n = 8)
Sample size: Approximately 2.5cm x 2.5cm
Inducing substance: Compound 48/80

Test method: The test was carried out with reference to the method of Kuraishi et al. (Maekawa T, Nojima H, Kuraishi., Jpn. J. Pharmacol. 84, 462-466 (2000)). That is, before the start of the test, the back of a mouse acclimatized in an acrylic cage for about 60 minutes was removed with a clipper, and the specimen was affixed and held with a non-woven adhesive bandage (mesh pore (registered trademark) tape). After 60 minutes, the specimen was removed, and compound 48/80 was administered intradermally (100 μg / site) to the specimen application site. Immediately after that, the mouse was returned to the cage and a movie was taken.

Evaluation method: From the reproduction of the captured video, the number of scratches in the hind limbs for the administration site for 15 minutes from the administration of Compound 48/80 was measured and used as an index of the antipruritic effect.

Dose The dose of each drug per animal is shown in Table 4.

Test The significant difference between each drug administration group and Group I (control group) was determined by the Dunnett method (Dunnett's multiple comparison test) (**: P <0.01).

Results FIG. 8 and Table 5 show the experimental results using the compound 48 / 80-induced mouse pruritus model. The data indicates the mean value ± standard error (SE). In FIG. 8 and Table 5, **: p <0.01 (Dunnett's multiple comparison test).

  As a result of comparison with the control group, a decrease in the number of scratches was observed between the diphenhydramine hydrochloride administration group and the promethazine hydrochloride administration group.

Example 7
(1) Polyethylene terephthalate (PET) hydroentangled nonwoven fabric (manufactured by Japan Vilene Co., Ltd., trade name EW-9400) was cut into 5 cm × 30 cm with a heat cutter, and then the cut carrier was dried with a vacuum desiccator, and its mass ( _Wi ) was measured with an electronic balance.
(2) a glass filter paper supercritical fluid extraction apparatus (JASCO Corporation, model number SCF-SRO Is) was cut to fit the size of the cells (columns) of was subjected to mass measurement (this mass was set to W _ii). The cell (column) volume of the used supercritical fluid extraction device (manufactured by JASCO, model number SCF-Sro) was 50 mL.
(3) A drug solution was prepared by dissolving dexamethasone (manufactured by Wako Pure Chemical Industries, Ltd.) in ethanol (99.5%, manufactured by Wako Pure Chemical Industries, Ltd.) to a concentration of 12.5 g / L.
(4) The drug solution prepared in (3) is added dropwise to the glass filter paper cut in (2) in such an amount that the drug is 5% by mass (5% owf) relative to the PET water-entangled nonwoven fabric as the carrier. And allowed to air dry.
(5) In a cell of a supercritical fluid extraction apparatus (manufactured by JASCO, model number SCF-Sro), a carrier (PET water-entangled nonwoven fabric) and (4) glass filter paper carrying a drug (dexamethasone) were placed. . After putting the cell into the device and raising the temperature and pressure in the cell to 60 ° C. and 10 MPa, carbon dioxide (liquefied carbon dioxide, purity 99.5% or more, manufactured by Uno Oxygen Co., Ltd.) is fed and injected into the carrier for 30 minutes. Went. After this injection treatment, the carrier and the glass filter paper carrying the drug (dexamethasone) were dried in a vacuum desiccator for 2 hours. The mass (W _sc ) of the carrier after drug injection was measured with an electronic balance. The surface of the carrier was stored in a dark place at room temperature without washing.
Samples were prepared twice by the above procedure, and samples (a) and (b) were obtained. For each specimen, no significant changes were observed in the appearance and characteristics of the carrier, and the air permeability was extremely high.

Similarly to Example 4, the mass change rate was calculated by the following equation.
Mass change rate (%) (ratio of mass change of treated PET nonwoven fabric) = 100 × (W _sc −W _i ) / W _i
Table 6 shows the results of injecting dexamethasone into the PET hydroentangled nonwoven fabric.

Example 8
Example 7 (5) was performed in the same manner as in Example 4 except that triamcinolone acetonide (manufactured by Wako Pure Chemical Industries, Ltd.) was used as the drug and the injection treatment was performed at 40 ° C. and 10 MPa for 30 minutes. The drug (triamcinolone acetonide) was injected into the carrier. In the same manner as in Example 7, the specimen was prepared twice to obtain specimen (c) and specimen (d). For each specimen, no significant changes were observed in the appearance and characteristics of the carrier, and the air permeability was extremely high.

  Table 7 shows the results of injecting triamcinolone acetonide into the PET hydroentangled nonwoven fabric.

  In the specimens (a) to (d) obtained in Examples 7 and 8, each specimen having a large mass change rate (dexamethasone is specimen (b) and triamcinolone acetonide is specimen (d)) is used. In Example 9 described later, a pharmacological test using a carrageenin-induced paw edema model was performed.

Example 9
The specimens produced in Example 7 and Example 8 were evaluated for drug efficacy by the following test method.
Carrageenin-induced paw edema suppression test animals: Rat (Wistar strain, male, 6 weeks old at delivery, manufactured by SLC Japan)
Number of cases and group composition Group I Untreated (control) group (n = 8)
Group II Fulvean Kowa (trade name “Flubean Kowa”, manufactured by Kowa Co., Ltd.) administration group (control group) (n = 8)
Group III Sample (b) (Dexamethasone-Injected Nonwoven Fabric) Administration Group (n = 8) Manufactured in Example 7
Group IV Sample (d) produced in Example 8 (triamcinolone acetonide-injected non-woven fabric) administration group (n = 8)
Sample size: 2.5cm x 2.5cm
Inflammator: 1% carrageenan / saline

Test procedure: The hair of the rat's legs was previously removed using a human hair removal cream on the day before the experiment day. The foot volume of the rat right hind limb was measured with a foot volume measuring device, 0.1 mL of a 1% carrageenan solution as an inflammation agent was administered subcutaneously to the footpad of the hind limb, and each specimen was affixed immediately thereafter.
Four hours after administration of the inflammation agent (specimen attachment), the specimen was removed, and the right hind paw volume was measured.

Evaluation method: The edema rate was calculated from the foot volume before and 4 hours after administration of the inflammatory agent, using the following formula as an index of the anti-inflammatory effect.

Dose The dose per animal is shown in Table 8.

Test The significant difference between each drug administration group with respect to Group I (no treatment (control) group) was determined by the Dunnett method (Dunnett's multiple comparison test) (**: P <0.01).

Results The test results are shown in Table 9 and FIG. The results in Table 9 and FIG. 9 are expressed as mean ± standard error (SE). **: p <0.01 (Dunnett's multiple comparison test)

When the untreated group (Group I) was compared with the control group and each sample group, significant efficacy was observed in the control group (Group II) and both sample groups (Group III and Group IV) (Dunnet's Multiple test).
When the specimens (formulations) produced in Examples 7 to 8 were used, edema was significantly suppressed as compared with the untreated first group (control).

Example 10
In the following procedure, a drug was injected into a carrier (nonwoven fabric) to prepare a specimen in which the drug was injected into the nonwoven fabric. Dibucaine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.) was used as the drug.
(1) Polyethylene terephthalate (PET) hydroentangled nonwoven fabric (manufactured by Japan Vilene Co., Ltd., trade name EW-9400) was cut into 5 cm × 30 cm with a heat cutter, and then the cut carrier was dried with a vacuum desiccator, and its mass ( _Wi ) was measured with an electronic balance.
(2) The glass filter paper was cut according to the cell size of a supercritical fluid extraction device (manufactured by JASCO, model number SCF-Sro), and mass measurement was performed. The cell (column) volume of the used supercritical fluid extraction device (manufactured by JASCO, model number SCF-Sro) was 50 mL.
(3) A drug solution was prepared by diluting dibucaine hydrochloride to 50 g / L using distilled water as a solvent.
(4) The drug solution prepared in (3) is added dropwise to the glass filter paper cut in (2) in such an amount that the drug is 5% by mass (5% owf) relative to the PET water-entangled nonwoven fabric as the carrier. The mass was measured.
(5) In a cell of a supercritical fluid extraction device (manufactured by JASCO, model number SCF-Sro), a glass filter paper carrying a carrier (PET water-entangled nonwoven fabric) and (4) drug (dibucaine hydrochloride) I put it in. Place the cell in the device, raise the temperature and pressure in the cell to 40 ° C and 15 MPa, then feed carbon dioxide (liquefied carbon dioxide, purity 99.5% or more, manufactured by Uno Oxygen Co., Ltd.) and inject it into the carrier for 30 minutes Went. After this injection treatment, the carrier into which the drug (dibucaine hydrochloride) was injected (PET water-entangled nonwoven fabric) was dried in a vacuum desiccator for 2 hours. After drying, the mass of the carrier after drug injection was measured with an electronic balance (this mass was designated as _Wii ). The surface of the carrier was stored in a dark place at room temperature without washing.
Samples were prepared twice by the above procedure, and samples (a) and (b) were obtained. For each specimen, no significant changes were observed in the appearance and characteristics of the carrier, and the air permeability was extremely high.

The mass change rate was calculated by the following formula.
The injection amount of the drug was confirmed by calculating the increased mass by the formula of W _ii -W _i . The mass change rate (%) (the ratio of the mass change of the treated PET nonwoven fabric) was determined by a calculation formula of 100 × (W _ii −W _i ) / W _i .
Table 10 shows the results of injecting dibucaine hydrochloride into the PET hydroentangled nonwoven fabric in Example 10.

Example 11
In Example 10, the same operation was performed except that procaine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.) was used instead of dibucaine hydrochloride, and the drug (procaine hydrochloride) was injected into the carrier. In the same manner as in Example 10, the specimen was prepared twice to obtain specimen (c) and specimen (d). For each specimen, no significant changes were observed in the appearance and characteristics of the carrier, and the air permeability was extremely high.
Table 11 shows the results of injecting procaine hydrochloride into the PET hydroentangled nonwoven fabric in Example 11.

Example 12
In the specimens (a) to (d) obtained in Examples 10 and 11, each specimen having a large mass change rate (specimen (b) for dibucaine hydrochloride and specimen (c) for procaine hydrochloride) is used. Thus, a pharmacological test using a formalin-induced mouse pain model was carried out by the following method.

Experimental method model: formalin-induced mouse pain model Animal used: mouse (ICR system, male, 4 weeks old at delivery, purchased from Japan SLC), body weight (16.9g-20.6g)
Number of cases and group composition:
Control group (polyethylene terephthalate (PET) water-entangled non-woven fabric (Nippon Vilene, trade name EW-9400)) (n = 6)
Procaine hydrochloride administration group (group to which sample (c) was cut into a predetermined size was attached) (n = 6)
Dibucaine hydrochloride administration group (group to which specimen (b) was cut into a predetermined size was attached) (n = 6)
Positive control group (lidocaine (trade name: xylocaine (registered trademark) jelly 2%, manufactured by AstraZeneca) was applied.) (N = 6), xylocaine (registered trademark) jelly 2% applied amount was 0.1 mL
Sample size: approx. 2cm x 3cm
Inducing substance: formalin Test method: Cowan ¹⁾ et al. That is, before the start of the test, the flank of a mouse acclimated for about 60 minutes in an acrylic cage was removed with an electric clipper and an electric shaver, a sample was attached, and then a non-woven adhesive bandage (mesh pore (registered trademark) tape) was used. I held it. The sample was removed 60 minutes after applying the sample. The site where the specimen was affixed was wiped off, and 2% formalin was administered intradermally (50 μL / site) to the specimen affixed site. Immediately after that, the mouse was returned to the cage and a movie was taken.
The drug (lidocaine (trade name: Xylocaine (registered trademark) jelly 2%, manufactured by AstraZeneca)) was administered to the positive control group as follows. 0.1 mL of the above drug is dropped onto the hair removal part of the mouse flank using a syringe (Terumo syringe (registered trademark)) and applied to a size of about 2 cm × 3 cm, and then an untreated non-woven fabric (PET water stream) This was covered with a composite nonwoven fabric (trade name EW-9400, manufactured by Nippon Vilene Co., Ltd.) and held with a nonwoven fabric adhesive bandage (mesh pore (registered trademark) tape).
1) Inan S, Dun NJ, Cowan A., Eur J Pharmacol. 616, 141-146 (2009)

Evaluation method: Stopping the total time (pain reaction time) showing pain response (biting [biting], licking [licking], etc. behavior, Fig. 10) to the administration site for 30 minutes after formalin administration from playback of the captured video It was measured with a watch and used as an index of the local anesthetic effect.

  Table 12 shows the dose of the drug per animal in the pharmacological test using the formalin-induced mouse pain model.

* The dose per model mouse was calculated from the following formula.
・ Drug injection amount (g) per non-woven fabric (5 × 30cm)
Drug injection volume (g) = Mass after injection (g)-Mass before injection (g)
- for the area of the nonwoven fabric is 150 cm ^2,
Drug amount per 1 cm ^{2 of} nonwoven fabric (mg / cm ² ) = Drug injection amount (g) ÷ 150 × 1000
• Since the adhesion area per animal is about 6cm ^2,
Dose per animal (mg) = Drug amount per 1 cm ² (mg / cm ² ) × 6

As an example, the results of calculating the drug injection amount, the drug amount per 1 cm ^{2 of} the nonwoven fabric, and the dose per animal when the sample (b) is attached to the sample (b) are shown. The mass before injection and the mass after injection are as shown in Table 10 above.
Drug injection amount (g) = 1.55684-1.55279
= 0.00405
Drug amount per 1 cm ² (mg / cm ² ) = 0.00405 ÷ 150 × 1000
= 0.027
Dose per animal (mg) = 0.027 x 6
= 0.162

Results The results are shown in FIG. The result shown in FIG. 11 is an average value. In FIG. 11, “control” is a control group, “procaine” is a procaine hydrochloride administration group, “dibucaine” is a dibucaine hydrochloride administration group, and “positive control” is a positive control group.
In both sample groups of the dibucaine hydrochloride group and the procaine hydrochloride group, a decrease in pain response time was observed compared to the control group.

  The present invention is useful in the medical field and the like.

Claims (12)

  A pharmaceutically effective chemical component is dissolved in a medium selected from either a supercritical fluid, a subcritical fluid, or water in a liquid state whose temperature exceeds 100 ° C., and the medium in which the chemical component is dissolved is dissolved. The manufacturing method of the external preparation characterized by including the injection | pouring process which inject | pours this chemical component into a support | carrier with this medium by making it contact with a support | carrier.   The production method according to claim 1, wherein the supercritical fluid or subcritical fluid is at least one selected from the group consisting of carbon dioxide, water, methane, ethane, propane, ethylene, propylene, methanol, ethanol, and acetone. .   The production method according to claim 1 or 2, wherein the supercritical fluid or subcritical fluid is a fluid substantially consisting of only carbon dioxide.   The pharmaceutically effective chemical component is at least one selected from the group consisting of non-steroidal anti-inflammatory drugs, antihistamines, local anesthetics, steroids, and antiallergic agents. The manufacturing method of crab.   The non-steroidal anti-inflammatory drug is at least selected from the group consisting of indomethacin or a salt thereof, felbinac, diclofenac or a salt thereof, loxoprofen or a salt thereof, ketoprofen or a salt thereof, flurbiprofen or a salt thereof, piroxicam, and meloxicam The antihistamine is at least one selected from the group consisting of diphenhydramine or a salt thereof, chlorpheniramine or a salt thereof, promethazine or a salt thereof, hydroxyzine or a salt thereof, and dimenhydrinate; The local anesthetic is at least one selected from the group consisting of lidocaine or a salt thereof, dibucaine or a salt thereof, procaine or a salt thereof, and mepivacaine or a salt thereof; a steroid agent is dexamethasone or a salt thereof, prednisolone, betamethaone And / or an antiallergic agent is at least one selected from the group consisting of diphenhydramine or a salt thereof, and promethazine or a salt thereof. 4. The production method according to 4.   The production method according to claim 1, wherein the carrier is formed from a material having air permeability.   The production method according to claim 1, wherein the carrier is formed from a fibrous substance.   The production method according to claim 1, wherein the carrier is a woven fabric or a nonwoven fabric formed from a fibrous substance.   Fibrous materials include rayon, cupra, acetate fiber, promix, nylon, polyester fiber, acrylic fiber, polyvinyl alcohol fiber, polypropylene fiber, polyethylene fiber, polyurethane fiber, polylactic acid fiber, cotton, hemp, wool, animal hair, and The production method according to claim 7 or 8, which is at least one fiber selected from the group consisting of silk.   The manufacturing method according to any one of claims 1 to 9, wherein the carrier has a cylindrical shape, a glove shape, or a sock shape.   The manufacturing method according to claim 3, wherein the injection step is performed under conditions of a temperature of 100 ° C. or less and a pressure of 10 to 25 MPa.   The external preparation manufactured by the manufacturing method in any one of Claims 1-11.