JP2013112671A - Transdermal medication device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a transdermal medication device capable of efficiently administering drug via a skin after a puncture by an MNA treatment.SOLUTION: The transdermal medication device for administering drug via the skin treated with a microneedle array is characterized in that the device includes a drug-containing hydrogel in which the drug is contained in the hydrogel, and that a percentage of stress relaxation of the drug-containing hydrogel in five minutes is 35-80%.

Description

  The present invention relates to a transdermal drug delivery device for administering a drug through a microneedle array (MNA) treated skin.

  The skin is a tissue that protects the living body from various external factors, and its outermost stratum corneum prevents the entry of various chemical substances into the body. The same applies to pharmacologically active substances (drugs), and it is difficult for many drugs to penetrate the skin except for nitroglycerin and nicotine. Therefore, as a device for the preparation, a search for a transdermal absorption enhancer that promotes the absorption of a drug has been conducted, and a great result has been achieved. However, in order to transfer a drug into the body by passive diffusion, the molecular weight of the drug itself is about 500, and the dosage is limited at present.

  On the other hand, pharmaceutical preparations that absorb drugs from the skin include matrix types in which the drug is dispersed and dissolved in a polymer such as an adhesive and then applied to the skin, as well as ions that transfer ionic drugs to the skin through a weak current. There are known administration methods such as tophoresis and electroporation for enlarging cell gaps by energizing the skin with a high-voltage current for a short time to promote drug transfer to the skin. Among these, with regard to the matrix type, since the stratum corneum of the skin, which is one of the defense tissues of the living body, is blocked, a drug having a large molecular weight can hardly penetrate the skin. On the other hand, according to iontophoresis, it has been confirmed that even a drug having a relatively large molecular weight can penetrate the keratin. However, the permeation of the epidermis may be rate limiting, and in the current situation, sufficient drug transfer cannot be realized. As for electroporation, the device is large and not always convenient for daily use. Therefore, as a method for administering a drug having a high molecular weight such as a peptide or an antibody drug, intravenous administration or subcutaneous injection is generally used. With regard to the injection needle for administering the drug solution by these injection administrations, although development of a fairly thin needle has been promoted, bleeding and pain are still involved at the time of puncture. For this reason, development of an injection needle that does not cause pain is desired, but satisfactory development has not yet been achieved.

  Therefore, development of a simpler and smaller transdermal drug administration device is desired, and in recent years, MNA having a needle height of several hundred microns has been developed, and many techniques have been proposed (for example, patent documents). 1). This MNA is a technology for manufacturing minute mechanical elements called MEMS (Micro-Electro-Mechanical Systems), which is indispensable for manufacturing semiconductors. Has been developed and used in experiments. Research is also being conducted on a method for efficiently administering a drug after skin puncture by MNA treatment. For example, as an administration method that devised MNA itself, MNA is directly molded using a water-soluble polymer in which the drug is dispersed, or the MNA is coated with a solution in which the drug is dissolved and the drug is applied at the time of puncture. A method of administration has been proposed. In addition, as a method for administering a drug from the skin surface after puncture by MNA treatment, an administration method in which absorbent cotton soaked with a chemical solution is placed on the puncture site is generally performed. Furthermore, a method of placing a drug-containing hydrogel containing a drug in a hydrogel instead of absorbent cotton on the puncture site is also known, but as such a drug-containing hydrogel, a gel having no shape retention property is used. It is used, and it is not known to use a gel having shape retention.

JP 2011-147807 A

  While the inventors proceeded to study a technique for administering a drug by placing a drug-containing hydrogel on the skin surface after puncture by MNA treatment, the present inventors have no shape-retaining property that has been conventionally used in the technique. In gels, it was found that the drug may not always penetrate the skin sufficiently.

  Therefore, the present invention has been made in view of the above problems, and an object of the present invention is to provide a transdermal drug administration device capable of efficiently administering a drug through the skin after puncture by MNA treatment.

  The inventors of the present invention have made extensive studies to solve the above problems. In the process, an attempt was made to administer a drug from the skin after MNA puncture using a drug-containing hydrogel having a certain degree of shape-retaining ability instead of the conventionally used gel having no shape-retaining ability. As a result, it was surprisingly found that the drug transdermal administration efficiency can be significantly improved by controlling the shape retention of the drug-containing hydrogel within a predetermined range. Then, the stress relaxation rate after 5 minutes was adopted as an index of the shape retention of the drug-containing hydrogel, and the present invention was completed.

  That is, according to the present invention, there is provided a transdermal drug administration device for administering a drug through the skin treated with a microneedle array. This transdermal drug administration device has a drug in a hydrogel. And a drug-containing hydrogel. The drug-containing hydrogel is characterized in that the stress relaxation rate after 5 minutes is 35 to 80%.

  ADVANTAGE OF THE INVENTION According to this invention, the transdermal drug administration device which can administer a drug efficiently through the skin after the puncture by MNA process can be provided.

It is a photograph which shows a time-dependent change of the puncture site | part (1 place) of the hairless mouse | mouth skin surface after the puncture by the microneedle array (MNA) process of length 0.5mm and cone-shaped tip diameter 0.1mm. In the examples, based on the results of in vitro skin permeation tests using various drug-containing hydrogels, the 1-hour cumulative permeation amount of lidocaine (μg / ml) with respect to the stress relaxation rate (%) after 5 minutes of the gel. cm ² ). In the Examples, based on the results of in vitro skin permeation tests using various drug-containing hydrogels, the 4-hour cumulative permeation amount of lidocaine hydrochloride (μg / g) with respect to the stress relaxation rate (%) after 5 minutes of the gel. cm ² ).

  Hereinafter, modes for carrying out the present invention will be described.

  One aspect of the present invention provides a transdermal drug delivery device for administering a drug through MNA treated skin.

  The transdermal drug administration device provided by the present invention has a drug-containing hydrogel in which a drug to be administered is contained in a hydrogel. And the point that the stress relaxation rate after 5 minutes of the said drug containing hydrogel is 35 to 80% is the biggest characteristic.

  As described above, conventionally, in a drug administration device using a hydrogel for administering a drug through MNA-treated skin, a non-type-retaining device has been used as the hydrogel. The reasons are as follows: (1) Gelation requires treatment for crosslinking, such as additives and electron beams, and does not have a good effect on drug stability; (2) Moisture is applied to absorbent cotton Liquid or uncrosslinked gel is likely to enter the puncture site (actually, the puncture hole closes, which is not preferable), and a liquid form or a similar dosage form is considered preferable Because it was. In addition, this hydrogel without a shape retention property is equivalent to what shows a stress relaxation rate close to 100% after 5 minutes, and is in a state like an ointment.

  As a drug administration method using a microneedle, there is a case where a drug-containing gel is coated on a needle for administration. However, this method is not suitable for a large amount of drug because the amount that can be coated is limited and the dose is limited.

  The present inventors have found that even when a drug is contained in a hydrogel having no shape retention as described above and the drug is administered from the skin after MNA treatment, the drug may not always sufficiently permeate the skin. I found it. Unlike conventional techniques, the hydrogel has moderate shape retention (controls the stress relaxation rate within a range of 35 to 80% after 5 minutes), thereby administering the drug from the skin after MNA treatment. They found that the efficiency was significantly improved. In addition, although the mechanism which improves administration efficiency by giving moderate shape-retaining property to hydrogel (controlling the stress relaxation rate in the range of 35 to 80% after 5 minutes) is not completely clear, The following mechanism is presumed. That is, the skin opening after puncturing by the MNA treatment is blocked by the elasticity inherent in the skin, but according to this embodiment, the drug-containing hydrogel has an appropriate shape retaining property. Thus, it is considered that the gel enters the skin opening after the puncture and prevents the skin from being blocked by the elasticity of the skin, thereby realizing a stable skin permeability.

  Hereinafter, each component of the transdermal drug administration device according to this embodiment will be described in detail.

[Drug-containing hydrogel]
The transdermal drug administration device according to this embodiment has a drug-containing hydrogel. The drug-containing hydrogel is a drug in which a drug to be administered is contained in the hydrogel.

  The drug contained in the drug-containing hydrogel is not particularly limited as long as it is desired to be administered transdermally. From this viewpoint, a drug with a large dose that is not normally supposed to be administered transdermally is not preferable. In addition, the stratum corneum, which is the largest barrier layer of the skin, is a fat-soluble film, and it is generally considered that a drug having fat solubility is more suitable as a drug having high transdermal absorbability. However, since the stratum corneum barrier is meaningless when the skin is directly perforated like microneedles, water-soluble drugs that are easier to distribute to the underlying water-soluble subcutaneous tissue than lipid-soluble drugs Is preferred as a drug. As the water-soluble drug, in addition to general water-soluble drugs, growth factors, hormones, cytokines, antigens, antibodies, fragments and analogs thereof can be exemplified as preferable drugs. As described above, according to the transdermal drug administration device according to this embodiment, efficient transdermal administration is possible even for drugs having a molecular weight of 500 or more, which have been difficult to administer transdermally in the prior art. There is an advantage that you can expect.

  Moreover, there is no restriction | limiting in particular also about the specific composition (component) of the hydrogel which comprises a medicine containing hydrogel, and conventionally well-known knowledge can be referred suitably. Typically, the hydrogel includes a base material made of a polymer and a solvent.

  As the polymer constituting the base material composed of the polymer, a water-soluble polymer suitable for holding a water-soluble drug is preferably contained as a main component of the base material. Here, “water-soluble polymer” is a general term for polymer compounds that are soluble in water. This water-soluble polymer contains a large number of functional groups having a polarity that strongly interacts with water in the molecule. Such water-soluble polymers include naturally occurring starch, gelatin, gellan gum, semi-synthetic carboxymethyl cellulose (CMC), cellulose derivatives such as methyl cellulose (MC), polyacrylamide (PAM), polyvinyl alcohol (PVA), poly An acrylic acid polymer, polyethylene oxide (PEO), etc. are mentioned. In the case where a water-soluble polymer is included as a “main component” of a base material made of a polymer, the proportion (mass ratio) of the water-soluble polymer in the base material made of the polymer is preferably 50% by mass or more. More preferably, it is 70 mass% or more, Especially preferably, it is 90 mass% or more, Most preferably, it is 100 mass%. When the polymer substrate contains a polymer other than a water-soluble polymer, examples of such a polymer include polyacrylic acid and its salts, polyvinylpyrrolidone and polysaccharides, aluminum stearate, dextran fatty acid ester, and the like. Can be mentioned.

  As a crosslinking agent for crosslinking the polymer chain of the water-soluble polymer as described above, a crosslinking agent such as boric acid and salts thereof, borax, formaldehyde, polyvalent ions, isocyanate compounds, and vinyl monomers are further included. May be. In addition, there is no restriction | limiting in particular also about the addition amount of such a crosslinking agent. Since the value of the stress relaxation rate after 5 minutes of the gel can also be controlled by adjusting the addition amount of the crosslinking agent, the crosslinking agent is adjusted so that the compression relaxation rate after 5 minutes of the gel is within a predetermined range. The addition amount of can be adjusted. As an example, the addition amount of the crosslinking agent may be about 0.1 to 30% by mass with respect to 100% by mass of the polymer substrate. In addition, cross-linking by freezing and low-temperature crystallization that repeats heat, ultraviolet rays, electron beams, freezing and low temperature may be performed alone or in combination.

  Moreover, as a solvent, it is common to contain components, such as water, lower alcohol (ethanol, methanol, isopropanol, n-butanol, etc.), polyhydric alcohol (ethylene glycol, glycerin, propylene glycol, etc.), especially water. Is preferably used as a solvent.

  In the above-described embodiment, there is no particular limitation on the content of each component (drug, polymer base material, solvent) constituting the drug-containing hydrogel, and the gel relaxation relaxation rate after 5 minutes is within a predetermined range. Thus, the solid content concentration of the gel can be adjusted. As an example, the content of the solvent in the drug-containing hydrogel is preferably 50 to 95% by mass, more preferably 60 to 95% by mass, particularly preferably 100% by mass based on the total amount of the drug-containing hydrogel. Is 70-90 mass%. In addition, the content of the base material composed of a polymer in the drug-containing hydrogel is preferably 1 to 50% by mass, more preferably 3 to 40% by mass with respect to 100% by mass of the total amount of the drug-containing hydrogel. Yes, particularly preferably 5 to 30% by mass. Note that the content of the drug in the drug-containing hydrogel may be appropriately set in consideration of the dose to be transdermally administered.

  As described above, the transdermal drug administration device according to this embodiment is characterized in that the stress relaxation rate after 5 minutes of the drug-containing hydrogel is 35 to 80%. It has been found that such a configuration improves the transdermal administration efficiency of the drug contained in the drug-containing hydrogel regardless of the type of base material (polymer) as a constituent material of the gel. It was done. In addition, as a value of “stress relaxation rate after 5 minutes”, it is calculated as a percentage of a change amount of a load after 5 minutes with respect to an initial load by applying a constant load to the gel and applying a probe to the gel in a column of an example described later. ) Shall be adopted. Here, when the stress relaxation rate after 5 minutes of the drug-containing hydrogel is less than 35%, the administration efficiency is lowered. This is because the gel becomes too elastic and the skin opening after puncture by MNA treatment It is thought that it is difficult for the gel to enter the site. On the other hand, even if the stress relaxation rate after 5 minutes of the drug-containing hydrogel exceeds 80%, the administration efficiency is still lowered, but this is because the gel plasticity is too high so that the open site of the skin after puncture will be closed. This is probably because the gel cannot sufficiently follow the inherent elasticity of the skin and the drug cannot sufficiently enter from the opening. The conventional drug-containing hydrogel having no shape-retaining property has a stress relaxation rate close to 100% after 5 minutes, which is different from the present invention (Sample 1 of Examples described later) And sample 6).

  The specific method for controlling the value of the stress relaxation rate after 5 minutes of the drug-containing hydrogel to a value within the range of 35 to 80% is not particularly limited. One example of means for achieving such control is adjusting the composition of the drug-containing hydrogel. For example, when the other conditions are the same, the content of the base material composed of the polymer constituting the hydrogel is relatively increased with respect to the content of the solvent, thereby reducing the stress relaxation rate after 5 minutes. Can be controlled in the direction of decreasing the value of. In addition, when a crosslinking agent is added, the value of the stress relaxation rate after 5 minutes can be controlled to decrease by increasing the amount of crosslinking agent added to increase the crosslinking density of the gel. Furthermore, it is possible to control the stress relaxation rate to increase (decrease) after 5 minutes by means of heating and cooling, cross-linking by light, radiation, plasma, catalyst, freezing and low-temperature crystallization. it can.

  Moreover, the initial load when obtaining the stress relaxation rate of the drug-containing hydrogel is preferably such that an appropriate load is obtained, and is about 0.01N to 2.0N, more preferably 0.01N to 1.2N. Even if the initial load is smaller or larger than this, the gel may not easily enter the skin opening after puncturing by the MNA treatment.

The size (thickness, projected area) of the drug-containing hydrogel is not particularly limited, but as an example, the thickness of the drug-containing hydrogel is appropriately set depending on the required drug concentration, sustainability, etc. It is about ˜5000 μm. The projected area of the drug-containing hydrogel is appropriately set according to the size of the area of the skin surface punctured by the MNA treatment, and is, for example, about 0.5 to ⁵ cm ² .

[Support]
The transdermal drug administration device according to the present embodiment has the above-described drug-containing hydrogel as an essential component, but the workability is poor only by the gel alone, so that the anchoring support is a sheet-like drug. You may arrange | position to one side of the containing hydrogel. By setting it as such a structure, workability | operativity at the time of handling a gel can be improved significantly.

  The material of the support is not particularly limited as long as it does not leak out components such as drugs contained in the drug-containing hydrogel. For example, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, vinyl chloride, polyurethane , Polyethylene terephthalate, polyesters such as polybutylene terephthalate, polyamides such as nylon, cellulose such as rayon, pulp, cotton or derivatives thereof, or a combination of two or more selected from materials such as polyacrylonitrile Yes, a woven fabric or a non-woven fabric made by entanglement, thermal fusion, pressure bonding or binder bonding is preferable. Among these, a nonwoven fabric of polyester (particularly polyethylene terephthalate) is preferably used because of its good anchoring property to hydrogel.

Further, the thickness of the support is preferably 0.001 to 1.5 mm, more preferably 0.5 to 1.0 mm, when measured with a pressure of 0.98 N per 5 cm ^{2 of} contact area. If the support is too thin, there is a tendency to cause shape breakage such as tearing, poor appearance due to leaching when placing the drug-containing hydrogel on the support, poor molding, and difficulty in sticking when the gel is applied. If the thickness is less than 0.1 mm, the tendency is particularly remarkable. Also, if the support is too thick, there is a tendency to cause a decrease in usability due to poor stretchability or poor flexibility of the support, turning over when applying the gel, and further increasing the cost as a material. This tendency is particularly remarkable.

  Furthermore, the color of the support is not particularly limited, but it has a great influence on the product image of the device, leading to improved aesthetics and usability when applied to the human body, so white, skin color, yellow, red, orange, etc. Can be mentioned as a preferred example, and the one with light and shade adjusted as necessary is more preferred. Processing such as printing and embossing is also possible as appropriate.

[Fixing adhesive tape]
Normally, the drug-containing hydrogel itself is not sticky, so when sticking to the skin, the device should be a device that is covered with a fixing adhesive tape on the support containing the drug-containing hydrogel or drug hydrogel laminated. Is particularly preferred. By fixing the drug-containing hydrogel with an adhesive tape for fixation, the drug-containing hydrogel enters the perforated hole with appropriate pressure applied to the skin, so that drug administration can be performed efficiently.

  The base material of the adhesive tape for fixing is not particularly limited. Polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, vinyl chloride, polyurethane, polyethylene terephthalate, polybutylene terephthalate, polyethylene Polyester such as naphthalate, polyamide such as nylon, polyacrylonitrile, cellulose or derivatives thereof, or a film or fabric (woven fabric, nonwoven fabric, knitted fabric) selected from one or more selected from materials such as metal foil such as aluminum Cloth) is preferred. In particular, polyurethane is preferably used.

  The substrate thickness of the fixing adhesive tape is preferably 1 to 200 μm, more preferably 5 to 150 μm, and still more preferably 10 to 100 μm. If the adhesive tape for fixing is too thin, it causes shape breakage such as tearing due to strength reduction and difficulty in sticking at the time of sticking. On the other hand, if the fixing pressure-sensitive adhesive tape is too thick, the usability is lowered, the film is turned over at the time of application, and a strange feeling is caused.

  In addition, for the purpose of improving the peelability or sticking property, the adhesive tape for fixing is sometimes used to process secant lines, perforations, carrier sheets, etc., and to improve the appearance and prevent film misalignment. It is necessary to carry out embossing or the like as appropriate.

  Various adhesives such as natural rubber, synthetic rubber, acrylic, silicone, polyvinyl alcohol, and polyamide can be used as the adhesive for the fixing adhesive tape. In this way, it is possible to obtain a relatively low skin irritation. Moreover, the thickness of the pressure-sensitive adhesive is preferably 5 to 200 μm, more preferably 5 to 50 μm. If the pressure-sensitive adhesive is too thin, the adhesive strength to the skin will be low, and it will easily fall off. On the other hand, when the thickness of the pressure-sensitive adhesive is too thick, a decrease in usability, adhesive residue, and a feeling of strangeness are caused.

  The fixing adhesive tape is preferably enclosed in a packaging material together with a release sheet of the same shape or more in a state where it is covered from above the drug-containing hydrogel or the support laminated on the drug-containing hydrogel. The adhesive tape itself may be attached and enclosed in the packaging material together with the hydrogel. When attaching the fixing adhesive tape, the release film cut to be larger than the area of the fixing adhesive tape is laminated on the adhesive surface.

  In addition, after the device in which the support and the drug-containing hydrogel are laminated is placed on the skin, the device can be fixed using a fixing tool such as Velcro (registered trademark) that wraps around the arm and the like. Considering the fixability of the drug-containing hydrogel, it is recommended to use the fixing adhesive tape described above.

[Release film]
A release film may be disposed for the purpose of protecting the surface opposite to the surface provided with the support of the drug-containing hydrogel or the fixing adhesive tape. This release film is peeled off during use. The material of the release film is not particularly limited, but polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, vinyl chloride, polyurethane, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, etc. Polyester such as polyester, nylon, polyacrylonitrile, cellulose or derivatives thereof, or a film formed by combining one or more selected from materials such as metal foil such as aluminum is preferable. In particular, polyethylene terephthalate is preferably used.

  The thickness of the release film is preferably 20 to 150 μm, more preferably 40 to 120 μm, and still more preferably 50 to 100 μm. If the release film is too thin, shape breakage such as tearing due to strength reduction, device manufacturing troubles, and difficulty in sticking at the time of applying the gel are caused. In addition, if the release film is too thick, the film is not suitable for cutting in device production, the film is turned over when the gel is applied, and the cost as a raw material is increased.

    In addition, the release film is processed for the purpose of improving peelability or adhesiveness, such as secanting, perforation, printing, etc., improving appearance and preventing film displacement, and taking out from packaging materials. For the purpose of facilitating, embossing or the like can be appropriately performed. Two or more release films may be used. Further, the surface of the release film on the drug-containing hydrogel side may be subjected to a treatment such as a silicone treatment for improving the release property.

  The release film may be cut to fit the size of the hydrogel, support, and fixing adhesive tape as necessary, but is usually formed larger than the fixing adhesive tape 1 It is preferable to use a single release film. In that case, in order to prevent the moisture of the drug-containing hydrogel from leaking out of the support, a recess may be provided near the center of the release film.

[Packaging bag]
From the viewpoint of preventing moisture volatilization, the transdermal drug administration device having the above-described configuration is, for example, polyethylene, polypropylene, polyethylene terephthalate, nylon, paper, and aluminum foil composite film, or aluminum until use. It is preferable to store in a heat-sealed packaging bag. In order to facilitate removal of the inside device, the interior of the packaging material can be subjected to sandblasting, embossing, silicone treatment, and the like.

[Production method]
The manufacturing method of the transdermal drug administration device according to this embodiment is not particularly limited, and the previously known knowledge about the production of the drug-containing hydrogel and the knowledge described above regarding the control of the stress relaxation rate after 5 minutes of the drug-containing hydrogel. Manufacture is possible by comprehensively considering the knowledge described in the examples described later. An example of the production method will be described. First, a predetermined amount of components (drug, polymer base material, solvent) constituting the gel are weighed and mixed to prepare a gel preparation solution. Next, the gel-containing hydrogel can be prepared by molding the obtained gel preparation solution into a desired size using a mold and solidifying the solution.

[Usage]
The transdermal drug administration device according to this embodiment is used for the purpose of administering a drug through MNA-treated skin.

  Prior to the use of the transdermal drug administration device of this embodiment, the MNA treatment is performed, but there is no particular limitation on the specific form of the MNA treatment, and the barrier function of the skin is temporarily suspended by puncturing a plurality of needles simultaneously. (See, for example, Wu, XM et al. (2006) J. Control Release, 118: 189-195, etc.).

There are no particular limitations on the constituent material of the microneedles constituting MNA, and for example, self-decomposing microneedles having a base composed of polylactic acid, polycaprolactone, or polyglycolic acid can be used. Such self-decomposing microneedles have high biocompatibility and can be used safely. The shape and size of the microneedle is not particularly limited, but is usually a conical shape such as a conical shape or a polygonal pyramid shape (such as a quadrangular pyramid shape). In this case, the area of the bottom surface of the triangular pyramid is 0.1 to It is about 0.5 mm ² and the height of the weight is about 0.4 to 0.5 mm.

  Here, FIG. 1 shows the change over time of the puncture site (one location) on the surface of the hairless mouse after puncture by the microneedle array (MNA) treatment with a length of 0.5 mm and a cone-shaped tip diameter of 0.1 mm. It is a photograph shown. As shown in FIG. 1, as time elapses immediately after puncturing, the skin opening is closed by the inherent elasticity of the skin. When a conventional drug-containing hydrogel with no shape retention (small shape retention) is intended for transdermal administration of a drug, the gel relaxes the stress when the opening is blocked in this way. It was difficult to do. On the other hand, by using the drug-containing hydrogel according to the present invention, the stress when the opening site is blocked can be relieved by the gel, and as a result, the drug can be efficiently administered from the opening site. It became.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to these. In this example, “%” in the composition ratio of the mixture means “mass%”.

[Sample preparation]
(Preparation of samples 1 to 4)
Polyvinyl alcohol (PVA) having the composition shown in Table 1 below and a half amount of water were heated in an autoclave at 90 ° C. for 60 minutes, and then uniformly mixed with a stirring blade. As PVA, model number PVA-117 (average polymerization degree 1700, saponification degree 98 to 99 mol%) manufactured by Kuraray Co., Ltd. was used. Subsequently, lidocaine hydrochloride (concentration: 10% with respect to the total amount of the gel preparation solution) and a half amount of water as a drug and an aqueous solution of the obtained PVA were mixed to prepare a gel preparation solution. It was applied to the surface of the PET support to a thickness of 1.5 mm. Samples 1 to 4 were prepared by freezing at −20 ° C. for 12 hours and then solidifying by thawing at 5 ° C. and molding to 15 mmφ.

(Preparation of samples 5-7)
Gelatin and a half amount of water having the composition shown in Table 1 below were heated in a water bath at 55 ° C. Next, an aqueous solution in which gellan gum, boric acid and half amount of water are mixed, and the resulting aqueous gelatin solution and lidocaine hydrochloride (concentration: 10% with respect to the total amount of the gel preparation solution) are mixed to prepare a gel preparation solution. did. In addition, Wako 1st grade made by Wako Pure Chemical Industries was used as gelatin, and Inagel GP-10 made by Ina Food Industry was used as gellan gum. It was applied to the surface of the PET support to a thickness of 1.5 mm. It solidified by cooling at 5 degreeC for 12 hours, and shape | molded to 15 mmphi, and prepared the samples 5-7.

(Preparation of samples 8-12)
Gelatin and a half amount of water having the composition shown in Table 2 below were heated in a 55 ° C. water bath. Next, an aqueous solution in which gellan gum, formaldehyde and a half amount of water were mixed, and the resulting gelatin aqueous solution, lidocaine hydrochloride (concentration: 10% with respect to the total amount of the gel preparation solution) as a drug were mixed to prepare a solution for gel preparation. . In addition, Wako 1st grade made by Wako Pure Chemical Industries was used as gelatin, and Inagel GP-10 made by Ina Food Industry was used as gellan gum. Samples 8 to 12 were prepared by coating the surface of the PET support to a thickness of 1.5 mm, solidifying by cooling at 5 ° C. for 12 hours, and molding to 15 mmφ.

[Evaluation of characteristics]
(Measurement of stress relaxation rate after 5 minutes)
For measuring the stress relaxation rate after 5 minutes, Tensilon model STA-1150 manufactured by ORIENTEC Co., Ltd. was used as a measuring device, the surface of the gel under the conditions of penetration rate: 50 mm / min, penetration distance: 2 mm, plunger: 22 mmφ. The load applied to was measured. The same measurement was performed immediately after the gel preparation and 5 minutes after the gel preparation, and the stress relaxation rate after 5 minutes was calculated according to the following formula 1 as the initial load and the load after 5 minutes, respectively. The same measurement was performed 5 times for each gel. The average (Ave.) and standard deviation (SD) values obtained as a result are shown in Tables 1 and 2 below.

(Skin penetration test)
First, as a microneedle array (MNA), an array of 45 (5 × 9) triangular pyramidal microneedles having a height of 0.45 mm and a bottom width of 0.25 mm made of polylactic acid was prepared.

  Using this MNA, the abdominal excised skin of a hairless mouse (male, 7 weeks old, Japan SLC) was punctured with a puncture pressure of about 2500 g. The punctured skin is attached to a vertical diffusion cell (inner diameter: 20 mmφ, capacity: about 16 mL), and the sample prepared above is placed on the puncture site of the skin so that the gel faces the skin. And fixed with Cateripe (registered trademark). Next, warm water heated to 32 ° C. was passed through the jacket of the diffusion cell, and physiological saline was added to the receiver solution to conduct a permeation experiment. After 1 hour and 4 hours from the loading of the gel, 0.5 mL each was sampled from the sampling port of the diffusion cell, and the centrifugal supernatant that had been deproteinized by adding the same amount of acetonitrile was collected as a sample and analyzed by HPLC. The amount of permeated drug was quantified. The measurement conditions by HPLC were as follows.

(HPLC measurement conditions)
Apparatus: LC-2010HT
Column: Mightysil RP-18 GP, 5 μm, 4.6 × 150 mm (Kanto Chemical)
Column temperature: 40 ° C
Injection volume: 20 μL
Flow rate: 1.5 mL / min
Detection wavelength: 230 nm
Mobile phase: 10 mM SDS, 20 mM phosphate buffer (pH 3.0) / acetonitrile = 11/9
The measurement results of the cumulative amount of lidocaine hydrochloride after 1 hour and after 4 hours are shown in Tables 1 and 2 below. The values listed in the table are the average value (Ave.) and standard deviation (SD) obtained by conducting the same experiment three times. In addition, for each sample, a graph in which the hourly cumulative permeation amount (μg / cm ² ) of lidocaine hydrochloride is plotted against the stress relaxation rate (%) after 5 minutes of the gel is shown in FIG. A graph plotting (μg / cm ² ) is shown in FIG.

  As shown in Tables 1 and 2 and FIGS. 2 and 3, when compared with gels having the same components (that is, Samples 1 to 4, Samples 5 to 7, and Samples 8 to 12, respectively), Samples having a stress relaxation rate in the range of 35 to 80% after 5 minutes showed larger values for the cumulative transmission after 1 hour and the cumulative transmission after 4 hours than for samples outside this range. Therefore, as in the present invention, by setting the stress relaxation rate after 5 minutes of the drug-containing hydrogel to a value within the above range, the drug is efficiently administered through the skin after puncture by MNA treatment. It has been shown that a transdermal drug delivery device can be provided.

Claims (4)

A transdermal drug administration device for administering a drug through a microneedle array treated skin,
Having a drug-containing hydrogel in which the drug is contained in a hydrogel;
A transdermal drug administration device characterized in that the stress relaxation rate after 5 minutes of the drug-containing hydrogel is 35 to 80%.   The transdermal drug administration device according to claim 1, wherein the drug is a water-soluble drug.   The transdermal drug administration device according to claim 1 or 2, wherein an adhesive tape for fixation is disposed so as to cover the drug-containing hydrogel or the support.   The transdermal drug administration device according to any one of claims 1 to 3, wherein the drug-containing hydrogel is enclosed in a packaging material together with an attached fixing adhesive tape.