JP2012254952A - Percutaneous absorption preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a percutaneous absorption preparation having high bioavailability of a target substance.SOLUTION: In the percutaneous absorption preparation having a support, and a plurality of conical or pyramid-shaped fine needles formed on the support and having a base comprising a high molecule substance with dissolvability in a body and stringiness and the target substance retained by the base, the support is hard and the fine needles have a first portion having a leading end part and containing the target substance, and a second portion having a bottom without containing the target substance. The first portion has length in an insertion direction shorter than length of the fine needles inserted into a body when administering the percutaneous absorption preparation.

Description

  The present invention relates to a percutaneously absorbable preparation having a support and a plurality of fine needles formed on the support for holding a target substance, and more particularly to the percutaneously absorbable preparation, wherein the support is made of a hard material. .

  As a preparation technique for transdermally administering a drug with high efficiency, a microneedle has been studied. The fine needle is a fine needle that does not feel pain even if it is stabbed into the skin. When a self-dissolving microneedle containing a drug is inserted into the body through the skin, the microneedle self-dissolves, whereby the drug is administered into the body.

  For example, Patent Document 1 describes that a fine needle is formed using a polymer substance that is soluble in the body and spinnable as a base. In Patent Document 2, in order to improve the bioavailability of the target substance contained in the fine needle, the fine needle is divided into a body insertion portion and a pressing portion, and the purpose is only for the body insertion portion. It describes the retention of substances.

  Patent Documents 1 and 2 also describe a percutaneous absorption preparation holding sheet in which a plurality of the fine needles are formed on a support such as a patch sheet.

  In a percutaneous absorption preparation having a support and a plurality of fine needles formed on the support for holding a target substance, the support is sheet-like and flexible, and the tip direction of the fine needles Change relatively freely. Therefore, when the fine needle is brought into contact with the skin and pressurized, the direction of the pressure hardly matches the insertion direction of the fine needle, and many fine needles that are not inserted into the skin are generated.

  When there are fine needles that do not penetrate the skin, the amount of the target substance administered into the body decreases, and as a result, the bioavailability of the target substance decreases. Therefore, the support is preferably formed from a hard material.

  That is, if the support is hard, the tip directions of the fine needles are aligned and fixed uniformly. Therefore, when the fine needle is inserted from the skin, the direction of the pressure easily matches the insertion direction of the fine needle, and the number of fine needles that are not inserted into the skin decreases.

  However, the skin is rich in flexibility and elasticity, and when the directions of a large number of microneedles are aligned and fixed, it is difficult to penetrate the microneedles sufficiently deep into the skin simply by applying pressure. Therefore, the penetration depth of the fine needle inserted into the skin at the time of administration of the transdermal absorption preparation becomes shallow, and many fine needle portions that are not inserted into the body remain.

  When the insertion depth of the fine needle inserted into the skin is shallow, the amount of the target substance administered into the body decreases, and as a result, the bioavailability of the target substance decreases. In addition, even when there are many fine needle parts that are not inserted into the body and the target substance is present in a part that is not inserted into the body of the fine needle, the target substance in that part is not administered into the body, and as a result The bioavailability of is reduced.

International Publication No. 2006/080508 International Publication No. 2009/066763

  The present invention solves the above-mentioned conventional problems, and an object of the present invention is to provide a percutaneous absorption preparation having a high bioavailability of the target substance.

The present invention relates to a conical or pyramid having a support, a base formed of a polymer substance that is soluble in the body and is spinnable, and a target substance held on the base. A percutaneous absorption preparation having a fine needle,
The support is rigid;
The fine needle has a first portion having a tip portion and containing a target substance, and a second portion having a bottom portion and no target substance,
The first portion has a length in the insertion direction that is equal to or less than the length of a fine needle that is inserted into the body during administration of the transdermally absorbable preparation.
A transdermally absorbable preparation is provided.

In one certain form, the said microneedle has a bottom diameter of 100-500 micrometers, and the insertion direction length of 100-700 micrometers, and exists on a support body with the density of 30-200 piece / cm < ² >.

  In one certain form, the said 1st part has a length of the insertion direction of 233 micrometers or less from the front-end | tip part of a fine needle.

  In one certain form, the said support body is obtained by tableting the excipient | filler for tablets.

  In one certain form, the substance which comprises the said base contains at least 1 type selected from the group which consists of sodium chondroitin sulfate, dextran, and hyaluronic acid.

  In one certain form, an impact force is applied and a fine needle is pierced into the skin.

In one certain form, the said impact force is applied by the collision pressure of 5-40N per 1.77cm < ² >.

  In one form, an impact force is applied and the fine needle is pierced into the skin, followed by secondary pressurization and the fine needle is pierced into the skin.

In one certain form, the said secondary pressure is 0.5-2.5N per 1.77 cm < ² >.

  The percutaneously absorbable preparation of the present invention has a deep penetration depth of the fine needle inserted into the body at the time of administration of the percutaneously absorbable preparation, and the target substance is localized in the portion of the fine needle inserted into the body. Therefore, a high bioavailability of the target substance is achieved.

It is a fragmentary perspective view which shows the structure of the percutaneous absorption preparation which is one Embodiment of this invention. It is a front view which shows an example of the fine needle used for the transdermal absorption preparation of this invention. It is a graph which shows the relationship between the applied speed, impact force, and penetration depth, when impact force is applied and a fine needle is inserted into the skin. In vitro, when the impact force is applied and the fine needle is inserted into the skin, the secondary pressure is further applied to insert the fine needle. It is a graph which shows the relationship between a pressure and penetration depth. In vivo, when the impact force is applied and the fine needle is inserted into the skin, the secondary pressure is further applied to insert the fine needle. It is a graph which shows the relationship between a pressure and penetration depth. It is a graph which shows the time transition of the hypoglycemic rate after administering the percutaneous absorption preparation and insulin solution of this invention which localized insulin at the front-end | tip part to a rat.

  FIG. 1 is a partial perspective view showing the structure of a transdermally absorbable preparation that is one embodiment of the present invention. This transdermally absorbable preparation has a support 1 and a plurality of conical fine needles 2 formed on the support.

  The support 1 is made of a material capable of firmly fixing the fine needle 2. The support 1 is insoluble in water. The support 1 is hard and does not substantially deform under a room temperature environment. Further, the support 1 is porous and does not hinder the drying of the fine needles in the course of forming the fine needles.

  A preferred support is a molded body comprising a porous plate of plastic such as polyethylene, polymethyl methacrylate, polyvinyl chloride and chlorinated polyethylene-styrene resin, and a water-insoluble tablet excipient.

  Among them, a preferable support is a molded body composed of a water-insoluble tablet excipient. This is because it is excellent in productivity and suitable for pharmaceutical manufacturing processes such as sterilization. The tablet excipient may be a composition containing a plurality of components. Preferred excipients for tablets include cellulose acetate, crystalline cellulose, cellulose derivatives, chitin and chitin derivatives.

  What is necessary is just to manufacture the molded object which consists of an excipient | filler for tablets similarly to a tablet. For example, a tablet excipient is put into a mortar of a tableting machine and tableted with a suitable tableting pressure using a punch. The dimensions of the support are appropriately adjusted by increasing or decreasing the diameter of the mortar, the filling amount of the tablet excipient, and the tableting pressure.

  The shape of the support is, for example, a disk shape having a diameter of 5 to 50 mm, preferably 10 to 35 mm, and a thickness of 1 to 10 mm, preferably 2 to 5 mm. The hardness of the support made of the excipient for tablets does not substantially change when the fine needle of the transdermal absorption preparation is pierced into the skin, and the percutaneous absorption preparation is applied to the skin by applying an impact force. There is no particular limitation as long as it does not collapse when the fine needle is pierced.

  A disc-shaped tablet support is placed on a metal cylinder having an outer diameter of 2.0 cm, an inner diameter of 1.2 cm, and a height of 2.0 cm, and is attached to the tip of a digital force gauge (FGP-50, Nidec Symposium). When the collapse strength is measured by attaching a conical attachment, in one embodiment, the collapse strength of the support is 30 to 50N. In this case, the thickness of the sample used for the measurement is 2 mm.

  FIG. 2 is a front view showing an example of a fine needle used in the transdermally absorbable preparation of the present invention. The fine needle is pointed and has a tip 3 that can penetrate the skin. Further, the fine needle is wide and has a bottom 4 fixed to the support. The shape of the fine needle may be a substantially conical shape or a substantially pyramid shape.

  The microneedle has a bottom diameter of 100-500 μm, preferably 150-400 μm, more preferably 200-350 μm, and a length in the insertion direction of 100-700 μm, preferably 150-600 μm, more preferably 200-550 μm. When the size of the fine needle is out of this range, the strength is insufficient or the penetration is deteriorated.

The fine needles are present on the support at a density of 30 to ²⁰⁰ / cm ² , preferably 60 to 160 / cm ² , more preferably 80 to 140 / cm ² . When the density of the fine needles is less than 30, the dose of the target substance tends to be insufficient. On the other hand, when the density of the fine needles exceeds 200, the resistance when the fine needles are inserted increases and the insertion depth becomes shallow.

  The fine needle has a first portion 21 and a second portion 22. The first part has a tip 3 and the second part has a bottom 4. Further, the first part and the second part form a boundary surface 5. The boundary surface between the first portion and the second portion is substantially parallel to or substantially parallel to the bottom surface of the fine needle.

  The first part of the microneedle contains the substance to be administered. The second part of the fine needle does not contain the target substance. And the 1st part has the length of the insertion direction below the length of the fine needle inserted in the body at the time of administration of this percutaneous absorption preparation. When the length of the first part in the insertion direction exceeds the length of the fine needle inserted into the body, the target substance present in the excess part is not administered into the body, resulting in a decrease in the bioavailability of the target substance. To do.

  Specifically, the length of the first portion in the insertion direction is 233 μm or less. In a preferred embodiment, it is difficult to insert a fine needle to a depth exceeding 233 μm during administration of a transdermally absorbable preparation. For example, the length of the first portion in the insertion direction may be 190 μm or less, or 160 μm or less. There is no need to consider the lower limit of the length of the first part. For example, in the case of a drug with an extremely small dose, the length of the first portion may be 10 μm.

  The percutaneous absorption preparation of the present invention is produced, for example, by forming a fine needle using a mold and then fixing the formed fine needle to a support. As the mold, a plate-like material provided with holes corresponding to the shape and arrangement of the fine needles is used. As the material of the plate-like material, fluororesin, silicon resin, ABS resin or the like is used.

  First, a base material, a target substance, and water, which are raw materials for the first portion of the fine needle, are mixed to prepare a first raw material mixture. As the base, a polymer substance that is soluble in the body and spinnable is used. By using the body-soluble polymer, the release efficiency of the target substance in the body is improved. In addition, the use of a spinnable polymer increases the strength of the fine needle and improves the penetration into the skin.

  As the polymer substance soluble in the body and spinnable, at least one substance selected from the group consisting of a polysaccharide having a leaky property, protein, polyvinyl alcohol, carboxyvinyl polymer, and sodium polyacrylate is used. In addition, about these polymeric substances, only 1 type may be used and you may use in combination of multiple types.

Preferably, the leaky polysaccharide is at least one selected from sodium chondroitin sulfate, dextran, dextran sulfate, hyaluronic acid, cyclodextrin, hydroxypropylcellulose, alginic acid, agarose, pullulan, glycogen and derivatives thereof. It is a substance.
0031
Preferably, the leaky protein is at least one substance selected from serum albumin, serum α-acid glycoprotein, collagen, low molecular collagen and gelatin and derivatives thereof.

  Particularly preferred in-vivo soluble and spinnable polymer substances include sodium chondroitin sulfate, dextran and hyaluronic acid.

  The target substance is not particularly limited as long as it is a substance that can be dissolved or dispersed in the polymer substance. For example, all substances such as a high molecular substance, a low molecular substance, a chemical substance, a physiologically active substance, a protein (recombinant or natural type), a peptide, and a polysaccharide can be used as the target substance. Preferably, it is a peptide, protein, nucleic acid, or polysaccharide. The target substance may be a cell, a drug, a vaccine, a nutrient, or a cosmetic ingredient.

  When the target substance is a drug or vaccine (antigen for vaccine), the preparation for body surface application of the present invention can be used for treatment, prevention, diagnosis and the like of diseases. Further, when the target substance is a cosmetic ingredient, it can be used for the purpose of preventing or improving skin aging, anti-aging, and maintaining skin whitening. Nutrients include, for example, health food and functional food ingredients.

  Next, the first raw material mixture is placed on a mold, and if necessary, coating pressure is applied using a coating tool or a coating device such as squeegee, and this is filled in a hole formed in the mold. In order to ensure filling, a centrifugal force may be applied to the mold using a centrifuge or the like.

  After removing the excess first raw material mixture, the first raw material mixture filled in the holes is dried. Drying is performed at a temperature of 50 ° C. or lower, preferably room temperature or lower, in order to prevent the target substance from being altered. After drying, the volume of the first raw material mixture decreases.

  Using this phenomenon, the length in the insertion direction of the first portion of the fine needle can be adjusted. That is, when preparing the first raw material mixture, the solid content concentration of the first raw material mixture is up to a height corresponding to the length in the insertion direction of the first portion of the fine needle after the first raw material mixture is dried in the mold. The concentration is adjusted to an appropriate level so that the solid content of the first raw material mixture remains.

  Next, the base material which is the raw material of the second part of the fine needle and water are mixed to prepare a second raw material mixture. Next, the second raw material mixture is placed on a mold filled with the dried first raw material mixture, and if necessary, this is filled into a hole formed in the mold using a coating tool or a coating device. Before the second raw material mixture is dried, a support is placed on the mold so as to come into contact with the second raw material mixture. The support is porous, and the components of the second mixture come into contact with the second mixture and penetrate into the pores inside the support by the anchor effect, thereby firmly bonding and absorbing the water contained in the second mixture. Can be released. In order to ensure filling, a centrifugal force may be applied to the mold using a centrifuge or the like. Next, the second raw material mixture filled in the holes is dried. Drying is performed at a temperature of 50 ° C. or lower, preferably room temperature or lower, in order to prevent the target substance from being altered. Thereafter, the percutaneous absorption preparation of the present invention is obtained by peeling the support from the mold.

  The obtained transdermally absorbable preparation is used for administering a target substance into a human or animal body. The administration method is as follows. First, the fine needle side surface (hereinafter referred to as “front surface”) of the percutaneous absorption preparation is directed to the skin, a predetermined impact force is applied to the skin, and the fine needle is inserted from the skin into the body. Let them enter. The skin is rich in elasticity and flexibility, and has a restoring force, so that it will come off when the fine needle is released immediately after impact.

  The impact force can be applied by causing the front surface of the transdermal preparation to collide with the skin at high speed. The pressure at which the percutaneously absorbable preparation collides with the skin (collision pressure) is 5 to 40 N, preferably 10 to 35 N, more preferably 15 to 30 N. When the impact pressure of the transdermally absorbable preparation is less than 15N, the insertion depth of the fine needle becomes shallow. Moreover, even if the collision pressure of the transdermally absorbable preparation is increased beyond 35 N, the penetration depth of the fine needle does not increase so much.

The collision pressure is a force per surface area of 1.77 cm ² because it was measured using a transdermal absorption preparation chip having an area of 1.77 cm ² that collides with the skin.

  The collision pressure can be adjusted, for example, by increasing or decreasing the speed at which the percutaneously absorbable preparation collides with the skin (collision speed). In one form, the impact velocity is 0.5 to 4 m / sec, preferably 1 to 3.5 m / sec, more preferably 2 to 3 m / sec.

  The method for colliding the transdermally absorbable preparation with the skin is not particularly limited. For example, the surface on which the fine needle of the percutaneous absorption preparation is not formed at the tip of the rod (hereinafter referred to as “rear surface”) is placed in an appropriate guide cylinder of a size that allows the rod to slide back and forth. The rod may be driven at a high speed with the front surface of the transdermal preparation facing the skin. The rod can be driven using an elastic body such as a spring and rubber, for example.

  After the fine needle is inserted into the skin by applying an impact force, further pressurization is applied from the back side of the transdermal absorption preparation (secondary pressurization). By doing so, the depth of the inserted fine needle becomes deeper. Further, the inserted fine needle is pushed back and maintained in the body without coming out. That is, the state where the entire first portion of the fine needle is inserted into the body is maintained. As a result, the bioavailability of the target substance is improved.

  The pressure of the secondary pressurization is 0.5 to 2.5N, preferably 1 to 2.5N, more preferably 1.5 to 2.5N. If the pressure is less than 0.1 N, the inserted microneedle may be pushed back, and the first portion of the microneedle may come out. Further, if this pressure is increased beyond 2.5 N, a burden such as pain on the skin occurs, which is not preferable.

The pressure of the secondary pressure is, the area of the portion in contact with the skin was measured using the percutaneously absorbable preparation chip 1.77 cm ^2, the force per area 1.77 cm ^2.

  The time for secondary pressurization is 1 to 5 minutes, preferably 2 to 3 minutes. When the pressurization time is less than 1 minute, the insertion depth of the fine needle does not increase. Further, even if the pressure is applied for more than 3 minutes, the penetration depth of the fine needle does not increase in proportion to the time, but almost reaches a peak.

  The following examples further illustrate the present invention, but the present invention is not limited thereto.

Reference example 1
(Puncture test to apply impact force)
A female mold made of silicon resin having 225 inverted conical pores having a depth of about 500 micrometers and an opening diameter of about 300 micrometers in a circle having a diameter of 1.5 centimeters was prepared. Moreover, 300 microliters of purified water was added to 100 mg of chondroitin sulfate sodium to prepare a viscous thick solution. After applying this thick viscous liquid onto the female mold hole and inserting it with squeegee under a pressure of about 3.0 MPa, rotate the whole female mold using a desktop centrifuge and use the centrifugal force. And filled under load. After drying, a thick viscous solution prepared by adding 300 microliters of purified water to 100 mg of chondroitin sulfate sodium salt was applied onto a female mold. Cellulose acetate for tablets was placed in a mortar of a single tableting machine, and a circular tablet base having a diameter of 1.5 cm and a thickness of about 2 mm prepared with a tableting pressure of about 10 kN was placed thereon, dried and cured. Thereafter, the base was peeled off from the female mold to obtain a percutaneous absorption preparation for insertion test which did not contain the target substance. The area of the surface in contact with the skin (front surface) of the percutaneous absorption preparation for penetration test is 1.77 cm ² .

  A test was conducted in which a fine needle of the obtained transdermally absorbable preparation was inserted into rat skin in vitro by applying a collision force. A commercially available disposable syringe “Terumo Syringe ss-20ESz” was prepared, and the tip of the syringe was opened. Subsequently, the back surface of the percutaneous absorption preparation was fixed to the tip of the injection rod, and was placed in a syringe with the tip open. A fine needle was made to collide with the rat skin by driving the injection rod with rubber toward the rat skin from which the front surface of the transdermal absorption preparation was peeled off. At that time, the impact pressure was changed to measure how the penetration depth of the fine needle changed. The result is shown in FIG.

  When the collision pressure was increased from 8.4 N to 21.3 N, the penetration depth increased from 20.8 μm to 63.2 μm. However, although the collision pressure was further increased to 40.2 N, the effect of increasing the penetration depth was not so much recognized.

  A similar test was conducted using human skin, but no significant difference was observed between the rat and human skin. Furthermore, under pentobarbital anesthesia, the percutaneous absorption preparation was made to collide with the abdominal hair removal skin of a rat, and the penetration depth was measured in an in vivo experiment, and the same result as the in vitro penetration test was obtained.

Reference example 2
(In vitro secondary pressure test)
A percutaneous absorption preparation for penetration test was produced in the same manner as in Reference Example 1, and fine needles were inserted into rat and human skin in vitro at a collision pressure of 21.3 N. Subsequently, the back side of the transdermal absorption preparation was pressurized (secondary pressurization). At that time, the pressure and pressurization time were changed to measure how the insertion depth of the fine needle changed. The result is shown in FIG.

  Increasing the secondary pressure increased the penetration depth proportionally. Also, when the secondary pressurization time was extended from 1 minute to 5 minutes, the penetration depth increased. There was no significant difference between rat and human skin.

Reference example 3
(In vivo secondary pressure test)
A percutaneous absorption preparation for penetration test was produced in the same manner as in Reference Example 1, and the percutaneous absorption preparation was collided with the abdominal hair removal skin of a rat under pentobarbital anesthesia at a collision pressure of 21.3 N. A fine needle was inserted into the rat skin. Subsequently, the back side of the transdermal absorption preparation was pressurized (secondary pressurization). At that time, the pressure and pressurization time were changed to measure how the insertion depth of the fine needle changed. The result is shown in FIG.

  As in Reference Example 2, it was found that the penetration depth into the skin increased as the secondary pressure and pressurization time increased to 1, 2, and 3 minutes. However, even if pressurization was performed for 3 minutes or more, no further increase in the penetration depth proportional to the pressurization time was observed.

  As a result of Reference Examples 1 to 3, the percutaneously absorbable preparation was applied with a collision pressure of 21.3 N to 40.2 N and allowed to pierce the skin, and then applied as a secondary pressurization with a pressure of 2.5 N for 3 minutes. Thus, it was possible to insert a length of 212 μm from the tip of the fine needle and a length of 233 μm from the tip of the fine needle into the body by applying a length of 10 minutes.

  Therefore, if the drug is localized at a portion of 233 μm from the tip of the microneedle, it becomes possible to achieve a value of 100% as the bioavailability of the target substance.

Example A silicon resin female mold having 225 inverted conical pores having a depth of about 500 micrometers and an opening diameter of about 300 micrometers in a circle having a diameter of 1.5 centimeters was prepared. In addition, after weighing 10 mg of insulin, 0.2 mg of Evans blue and 10 mg of sodium chondroitin sulfate, 70 and 75 microliters of degassed purified water was added to prepare viscous thick solutions, respectively. After applying this thick viscous liquid onto the female mold hole and inserting it with squeegee under a pressure of about 3.0 MPa, rotate the whole female mold using a desktop centrifuge and use the centrifugal force. And filled under load. After drying, a thick viscous liquid prepared by adding 400 microliters of purified water to 440 mg of chondroitin sulfate sodium salt was applied onto a female mold. Cellulose acetate for tablets was put in a mortar of a single tableting machine, and a tablet base having a diameter of about 1.5 cm and a thickness of about 2 mm prepared with a tableting pressure of about 10 kN was placed on the tablet, and dried and cured. Thereafter, the base was peeled off from the female mold, and two transdermal absorption preparations having fine needles containing insulin as a target substance were obtained.

  The two needles of the two-layer microneedle array chip transdermal preparation prepared were observed with a video microscope (VH-5500, Keyence, Inc.), and the length from the tip of the first part colored blue Was measured. 181.2 ± 4.2 micrometers and 209.5 ± 3.9 micrometers.

  The insulin content in both formulations was 1.58 ± 0.03 and 1.72 ± 0.13 IU. FIG. 4 shows the results of verifying the effectiveness by administering to the depilation abdominal skin of rats. As a control formulation, 1.0 unit of insulin solution was administered to rats by subcutaneous injection. FIG. 6 shows the measurement results of the time course of the circulating plasma glucose concentration in rats. ● are data for injections, and ○ and Δ are data for two-layer microneedle array tips with a packing length of about 180 microns and about 210 microns. When the value of hypoglycemic area after administration of insulin microneedle array chip preparation and injection to rats was compared, the pharmacological availability (RPA) was 98.07 ± 0.8% and 98.08, respectively. It was ± 3.1%.

1 ... support,
2 ... fine needles,
21 ... 1st part,
22 ... the second part,
3 ... the tip,
4 ... Bottom,
5 ... Boundary surface.

Claims (9)

A conical or pyramidal microneedle having a support, a base made of a polymer substance that is soluble in the body and spinnable, and a target substance held on the base, formed on the support A transdermally absorbable preparation comprising:
The support is rigid;
The fine needle has a first portion having a tip portion and containing a target substance, and a second portion having a bottom portion and no target substance,
The first portion has a length in the insertion direction that is equal to or less than the length of a fine needle that is inserted into the body during administration of the transdermally absorbable preparation.
Transdermal absorption preparation. The percutaneous absorption according to claim 1, wherein the fine needle has a bottom diameter of 100 to 500 µm and an insertion direction length of 100 to 700 µm, and is present on the support at a density of 30 to ²⁰⁰ / cm ^2. Formulation.   The percutaneous absorption preparation according to claim 1 or 2, wherein the first portion has a length in the insertion direction of 233 µm or less from the tip of the fine needle.   The percutaneous absorption preparation according to any one of claims 1 to 3, wherein the support is obtained by tableting a tablet excipient.   The transdermally absorbable preparation according to any one of claims 1 to 4, wherein the substance constituting the base comprises at least one selected from the group consisting of sodium chondroitin sulfate, dextran and hyaluronic acid.   The percutaneous absorption preparation according to any one of claims 1 to 5, wherein an impact force is applied and a fine needle is inserted into the skin. The percutaneous absorption preparation according to claim 6, wherein the impact force is applied by a collision pressure of 5 to 40 N per 1.77 cm ² .   The impact force is applied, the fine needle is inserted into the skin, and then the secondary pressure is applied, and the fine needle is inserted into the skin. Transdermal absorption preparation. Percutaneous absorption preparation according to claim 8 wherein the secondary pressure is 0.5~2.5N per 1.77 cm ^2.

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