JP5636715B2 - Transdermal absorption preparation - Google Patents

Description

  The present invention relates to a matrix-type transdermal absorption preparation containing a diuretic.

Diuretics are classified into thiazide diuretics, thiazide analogs, loop diuretics, potassium-sparing diuretics and carbonic anhydrase inhibitors, depending on their chemical structure and mechanism of action. Although diuretics are treated for edema and hypertension, thiazide diuretics and thiazide analogs are particularly frequently used as antihypertensive diuretics. These thiazide diuretics and thiazide analogs inhibit the Na ⁺ / Cl ⁻ (sodium ion / chloride ion) cotransport system present in the luminal membrane at the beginning of the distal tubule, and Na ⁺ It is known to exhibit diuretic action and antihypertensive action in order to suppress reabsorption.
Currently, trichlormethiazide, hydrochlorothiazide and the like are used as treatments for essential hypertension as thiazide diuretics, and among them, trichlormethiazide is one of the most frequently used drugs. Antihypertensive diuretics are thought to be useful in combination therapy with antihypertensive drugs in Japan, where the intake of salt is high, and the drug price is relatively low.

  From the results of recent large-scale clinical trials, it has been found that thiazide diuretics and thiazide analogs exhibit antihypertensive effects at relatively low doses. On the other hand, it has become clear that side effects on the metabolic system (hypokalemia, hyperuricemia, hyperlipidemia, decreased glucose tolerance, etc.) increase in a dose-dependent manner. For this reason, the guideline has already recommended the use of thiazide diuretics at low doses in the West.

  In addition, oral administration generally has a sharp rise in plasma concentration after administration, but rapid diuresis in the elderly adversely affects circulatory dynamics, diminishing plasma volume, dehydration, dizziness due to hypotension, etc. May cause dizziness. In particular, when an elderly person with heart disease or the like has a rapid diuretic effect, blood concentration occurs due to a rapid decrease in plasma volume, which may induce thromboembolism (see Non-Patent Document 1). For this reason, it is considered desirable for diuretics to aim at slow diuresis by keeping the active ingredient at a constant plasma concentration while suppressing a transient rapid increase in plasma concentration. .

  In general, transdermal preparations, especially patches with an adhesive matrix layer containing a drug on one side of a support such as a plastic film, are used for drug metabolism due to the first-pass effect of the liver and transients after drug administration. It is known that various side effects due to an increase in the plasma concentration of can be avoided, and the drug can be administered continuously over a long period of time. In addition, advantages such as a reduction in the number of administrations, improvement in compliance, ease of administration and discontinuation, and the like are expected, and it is known to be particularly useful for elderly and pediatric patients. Therefore, it is considered that the above problem can be solved by providing a patch of a thiazide diuretic or a thiazide analog.

  However, in general, the skin permeability of drugs is extremely low, and the only drugs that have been put to practical use for the purpose of systemic action so far are limited drugs such as isosorbide nitrate, nitroglycerin, scopolamine, and estradiol. To date, several techniques relating to transdermally absorbable preparations containing diuretics have been proposed.

  Ropot et al. In the composition of loop diuretics for transdermal therapeutic systems and their preparation, the degree of delay in the release of loop diuretics from the osmotic system is determined by the mixing ratio of fatty acid alkanolamide and carboxylic acid ester. Is disclosed (see Patent Document 1). However, this technique is considered to be intended for liquids and creams, as exemplified by the use of a suspension composition. Liquids and creams are systemic drugs that require precise dosage control such as diuretics, and are practical for continuous administration while maintaining the active ingredient at a constant plasma concentration over a long period of time. Not right. Further, although it is stated that it can be used in a reservoir-type transdermal preparation, no specific examination has been made, and there is no description or suggestion of a matrix-type transdermal absorption preparation such as a patch.

  Ren et al. Disclosed a transdermal patch (see Non-Patent Document 2) containing indapamide, a thiazide analog. However, this patch showed a transient and rapid increase in plasma concentration similar to that of oral preparations after administration, and in order to avoid adverse effects on the circulatory dynamics due to rapid diuretic action, Whether it can be administered continuously while maintaining a medium concentration has not been studied. In addition, this patch uses N-dodecylazepan-2-one (Aison) in order to enhance the transdermal absorbability of indapamide. Because of the fact that it may have an antiviral effect, and because of the fact that it was not approved as an additive by the US Food and Drug Administration (FDA) Possible (see Non-Patent Documents 3 and 4).

  Thus, in a transdermal preparation containing a thiazide diuretic or a thiazide analog, the active ingredient has excellent transdermal absorbability and is continuously administered while maintaining the active ingredient at a constant plasma concentration. In fact, a matrix-type transdermal absorption preparation that can suppress the transient rapid increase in plasma concentration observed after oral administration has not yet been completed.

Japanese Patent Laid-Open No. 62-283936

Internal Medicine Cardiovascular Protocol, Vol.75, No.5, pp. 747-761, 1995 International journal of pharmaceuticals, USA, ELSEVIER, in press (Available online 7 December 2008) Advanced Drug Delivery Reviews, 56 (5), pp. 603-618, 2004 Drug Development And Industrial Pharmacy, 32 (3), pp. 267-286, 2006

  The present invention contains a thiazide diuretic or a thiazide analog as an active ingredient, is excellent in transdermal absorbability of the active ingredient, and can be continuously administered while maintaining the active ingredient at a constant plasma concentration. Another object of the present invention is to provide a transdermal patch capable of suppressing a transient rapid increase in plasma concentration observed after oral administration.

  As a result of intensive studies to solve the above problems, the present inventor has a carboxyl group in the side chain in the monomer constitutional unit in the development of a patch containing a thiazide diuretic or a thiazide analog ( By containing thiazide diuretic or thiazide analog as an active ingredient and alkylglycoside or alkylthioglycoside as a percutaneous absorption enhancer in an acrylic adhesive base containing a copolymer containing a (meth) acrylate ester The present inventors have found that the drug can exhibit excellent percutaneous absorption without causing the above problems, and have completed the present invention.

That is, the present invention includes the following components (A), (B) and (C):
(A) a thiazide diuretic or a thiazide analog,
(B) alkylglycoside or alkylthioglycoside,
(C) Provided is a matrix-type transdermal absorption preparation containing an acrylic adhesive base containing a copolymer containing a (meth) acrylic acid ester having a carboxyl group in a side chain in a monomer structural unit.

  According to the present invention, the active ingredient is excellent in transdermal absorbability, and can be continuously administered while maintaining the active ingredient at a constant plasma concentration. Since an increase in plasma concentration can be suppressed, it is possible to provide a matrix-type transdermal absorption preparation that provides a stable therapeutic effect in the treatment of hypertension.

3 shows the time course of plasma trichlormethiazide concentration in rats to which the matrix-type transdermal absorption preparation of the present invention was applied.

  The matrix-type transdermal preparation of the present invention (hereinafter also referred to as a patch) is usually a patch in which a support layer, an adhesive layer and a release liner layer for protecting the surface of the adhesive layer are laminated in order. It is. The pressure-sensitive adhesive layer comprises (A) a thiazide diuretic or a thiazide analog as an active ingredient, (B) an alkyl glycoside or alkylthioglycoside as a transdermal absorption enhancer, and (C) a side in a monomer constituent unit as an adhesive base. It contains an acrylic adhesive base containing a copolymer containing a (meth) acrylic acid ester having a carboxyl group in the chain.

  Examples of thiazide diuretics to be blended in the patch of the present invention include ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penfluzide, polythiazide, methycrothiazide and the like. Examples of thiazide analogues include indapamide, chlorthalidone, tripamide, meticran, metolazone, and mefluside. Of these, thiazide diuretics are more preferable, and trichlormethiazide is particularly preferable in that it has excellent transdermal absorbability and maintains a constant plasma concentration for a long time.

  The content of the thiazide diuretic or thiazide analog contained in the patch of the present invention is not particularly limited as long as the pharmacological effect is obtained, but if it is too small, the medicinal effect cannot be secured, and if it is too much Since the drug precipitates on the pressure-sensitive adhesive layer and reduces the physical properties of the pressure-sensitive adhesive, it is preferably contained in an amount of 0.1 to 30 parts by weight when the entire pressure-sensitive adhesive layer is taken as 100 parts by weight. More preferably, it is 0.1-10 weight part, Most preferably, it is 0.1-5 weight part.

  The (B) alkylglycoside or alkylthioglycoside blended in the patch of the present invention has the effect of promoting transdermal absorption of the active ingredient (A). As shown in Examples and Comparative Examples described later, when an alkylthioglycoside or an alkylglycoside is blended, the absorption of thiazide diuretics and thiazide analogs is significantly better than when other transdermal absorption enhancers are blended. Promoting action is obtained.

Examples of the alkyl glycoside or alkylthioglycoside include C ₆ -C ₂₂ alkyl glycoside or C ₆ -C ₂₂ alkyl thioglycoside, among which C ₆ -C ₂₂ alkyl thioglycoside is more preferable. As a structure of this glycoside part, any of glucopyranoside (glucoside) and maltopyranoside (maltoside) may be sufficient. Examples of the alkyl glycoside or alkylthioglycoside include n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltopyranoside, n-heptyl-β-D-thio. Glucopyranoside, n-nonyl-β-D-thiomaltopyranoside, n-octyl-β-D-glucopyranoside, n-octyl-β-D-maltopyranoside, n-octyl-β-D-thioglucopyranoside, n-heptyl -Β-D-glucopyranoside, n-octyl-α-D-glucopyranoside, n-nonyl-β-D-thioglucopyranoside, n-decyl-β-D-thiomaltopyranoside, n-dodecyl-α-D- Examples thereof include maltopyranoside and n-dodecyl-β-D-thiomaltopyranoside. Particularly preferred is n-octyl-β-D-thioglucopyranoside.

  The content of the (B) alkylglycoside or alkylthioglycoside is not particularly limited, but if it is too small, the effect of promoting percutaneous absorption of the drug cannot be obtained, and if it is too large, the compatibility with the base is lowered. However, since the physical properties of the adhesive are lowered, it is preferable to contain 0.1 to 30 parts by weight when the entire pressure-sensitive adhesive layer is taken as 100 parts by weight. More preferably, it is 0.1-10 weight part, Most preferably, it is 0.1-5 weight part. In addition, the content ratio (A / B) of the component (A) and the component (B) is 0.1 to 10, more preferably 0.5 to 5, and particularly preferably from the viewpoint of transdermal absorption promoting effect and skin irritation. 5-3 are preferable.

  The acrylic adhesive base used in the present invention is not particularly limited as long as it is a copolymer containing a (meth) acrylic acid ester having a carboxyl group in the side chain in the monomer structural unit. ) Acrylic acid / (meth) acrylic acid alkyl copolymer, (meth) acrylic acid / (meth) alkyl acrylate / vinyl acetate copolymer, etc., specifically acrylic acid / 2-ethylhexyl acrylate Copolymer, acrylic acid / butyl acrylate copolymer, acrylic acid / octyl acrylate copolymer, acrylic acid / -2-ethylhexyl acrylate / vinyl acetate copolymer, methyl acrylate / methacrylic acid copolymer, Examples include methacrylic acid / n-butyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, and the like. Commercially available commercial products include DURO-TAK® 87-2979, 87-2074, 87-235A, 87-2100, 87-200A, 87-2852, 87-2051, 87-2052, 87. -2054, 87-2825, 87-2679, 87-2194, 87-2196 (National Starch & Chemical Company), GMS (trademark) 1430, 1753 (Cytec Industries Inc.), etc. are available. Moreover, you may add a crosslinking agent as needed. The crosslinking agent is not particularly limited, and examples thereof include amino compounds, phenol compounds, epoxy compounds, isocyanate compounds, organic peroxides, metal alcoholates, and metal chelates.

  As described above, the (A) thiazide diuretic or thiazide analog, (B) alkylglycoside or alkylthioglycoside and (C) a (meth) acryl having a carboxyl group in the side chain in the monomer structural unit as described above By including an acrylic adhesive base containing a copolymer containing an acid ester, the active ingredient has excellent transdermal absorbability, and the active ingredient can be continuously administered while maintaining a constant plasma concentration. It is possible to suppress the transient rapid increase in plasma concentration observed after oral administration.

  In the adhesive layer of the patch of the present invention, in addition to the components (A), (B) and (C), a plasticizer, an antioxidant, Fillers, drug solubilizing agents, antibacterial agents, skin irritation reducing agents, and the like can be appropriately blended.

  The plasticizer is not particularly limited, and examples thereof include glycols such as ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol; and fats and oils such as olive oil, castor oil, squalene, and lanolin. Hydrocarbons such as liquid paraffin; diisopropyl adipate, diisobutyl adipate, benzyl benzoate, cetyl 2-ethylhexanoate, oleyl oleate, decyl oleate, benzyl acetate, diisopropyl sebacate, diethyl sebacate, trioleic acid Sorbitan, sorbitan tristearate, cetyl palmitate, octyldodecyl myristate, cetyl myristate, myristyl myristate, isopropyl myristate Which fatty acid esters, and the like, can be incorporated into them one or more adhesive layers. The content of the plasticizer is preferably 20 to 80 parts by weight, and more preferably 30 to 70 parts by weight when the entire pressure-sensitive adhesive layer is 100 parts by weight. The antioxidant is not particularly limited. For example, a chelating agent such as sodium edetate, an ascorbic acid derivative such as sodium sulfite, butylhydroxyanisole, butylhydroxytoluene, ascorbyl tetraisopalmitate, acetic acid, and the like. Tocopherol derivatives such as tocopherol, quinoline derivatives such as oxyquinoline sulfate and the like can be mentioned. The filler is not particularly limited, and examples thereof include kaolin, bentonite, and titanium dioxide. The drug solubilizer is not particularly limited, and examples thereof include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and the like. The antibacterial agent is not particularly limited, and examples thereof include benzalkonium chloride, benzoic acid, methyl parahydroxybenzoate and the like. The skin irritation reducing agent is not particularly limited, and examples thereof include silicic anhydride.

  In the patch of the present invention, a support layer, an adhesive layer, and a release liner layer for protecting the surface of the adhesive layer are laminated in order.

  As the support of the present invention, polyester resin, polyethylene resin, polypropylene resin, polyvinyl chloride resin, polycarbonate resin, polyurethane resin, polyimide resin, synthetic resin film made of ethylene / vinyl acetate copolymer, natural fiber, synthetic resin Single layers such as fibers or fabrics / woven fabrics of these composite fibers, woven fabrics, nonwoven fabrics, paper, synthetic paper, metal foil, and laminates thereof are used. The support may be subjected to surface treatment such as primer treatment or water repellent treatment as necessary.

  As the release liner of the present invention, paper that has been subjected to release treatment by application of silicone resin or fluorine resin, paper laminated with a synthetic resin such as polyethylene resin, a synthetic resin film, or the like is used.

  The patch of the present invention can be produced by a method for producing an ordinary patch. For example, a base composition containing a drug is dissolved in an appropriate organic solvent such as acetone or ethyl acetate, the resulting adhesive solution is applied onto a support, and the organic solvent is dried and removed to form an adhesive layer. It can be manufactured by forming and then bonding a release liner on the pressure-sensitive adhesive layer. Alternatively, the pressure-sensitive adhesive solution may be coated on a release liner, an organic solvent is dried and removed to form a pressure-sensitive adhesive layer, and then a support is bonded onto the pressure-sensitive adhesive layer. . In addition, when forming the pressure-sensitive adhesive layer, if the pressure-sensitive adhesive solution is thickly applied at once, it may be difficult to dry uniformly. You may divide and coat.

  Further, the features of the present invention will be described in detail with reference to examples and comparative examples. These can be variously modified without departing from the technical idea of the present invention.

Example 1
Trichloromethiazide 2.0 parts by weight, n-octyl-β-D-thioglucopyranoside 3.0 parts by weight, isopropyl myristate 40.0 parts by weight, aluminum acetylacetonate 0.4 parts by weight, and acrylic adhesive base ( 54.6 parts by weight of National Starch & Chemical Company, trade name: DURO-TAK (registered trademark) 87-2852) were mixed and stirred uniformly in the container to obtain a uniform coating solution.
This coating solution was applied to one side of a polyethylene terephthalate film (thickness 12 μm) as a support so that the thickness after drying was about 90 μm, and this was dried at 60 ° C. for about 1 hour to give an adhesive base A layer was formed.
Next, a silicone-coated surface of a polyethylene terephthalate film (thickness 75 μm) as a separator was bonded to the adhesive base layer formed above and cut into a predetermined size to obtain a transdermally absorbable preparation of the present invention. .

Comparative Example 1
A percutaneous absorption preparation was obtained under the same conditions and method as in Example 1 using N-dodecylazepan-2-one (Aison) instead of n-octyl-β-D-thioglucopyranoside used in Example 1. .

Comparative Example 2
A percutaneous absorption preparation was obtained under the same conditions and method as in Example 1 except that 1-octyl-2-dodecanol was used instead of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 3
A percutaneously absorbable preparation was obtained under the same conditions and method as in Example 1 except that diethyl sebacate was used instead of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 4
A percutaneously absorbable preparation was obtained under the same conditions and method as in Example 1 except that polyoxyethylene (4) lauryl ether was used instead of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 5
A percutaneous absorption preparation was obtained under the same conditions and method as in Example 1 except that capric acid was used in place of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 6
A percutaneous absorption preparation was obtained under the same conditions and method as in Example 1 except that sorbitan monooleate was used instead of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 7
A percutaneous absorption preparation was obtained under the same conditions and method as in Example 1 using propylene glycol monocaprylate instead of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 8
A percutaneous absorption preparation was obtained under the same conditions and method as in Example 1 using squalane instead of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 9
A percutaneous absorption preparation was obtained under the same conditions and method as in Example 1 using L (-)-menthol instead of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 10
A percutaneous absorption preparation was obtained under the same conditions and method as in Example 1 except that DL-malic acid was used in place of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 11
A transdermally absorbable preparation was obtained under the same conditions and method as in Example 1 except that urea was used instead of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 12
A percutaneous absorption preparation was obtained under the same conditions and method as in Example 1 using N-methyl-2-pyrrolidone instead of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 13
A transdermally absorbable preparation was obtained under the same conditions and method as in Example 1 except that oleic acid diethanolamide was used instead of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 14
A transdermally absorbable preparation was obtained under the same conditions and method as in Example 1 except that lauric acid diethanolamide was used instead of n-octyl-β-D-thioglucopyranoside used in Example 1.

Comparative Example 15
The n-octyl-β-D-thioglucopyranoside used in Example 1 was not added, but instead the adhesive base was increased, and a percutaneous absorption preparation was obtained under the same conditions and methods as in Example 1.

Test Example 1 (in vitro skin permeation test using hairless mouse skin)
The percutaneously absorbable preparations obtained in the examples and comparative examples were punched into a circle having a diameter of 13 mm and used for the test. Seven-week-old male hairless mice were anesthetized and killed with diethyl ether, and immediately the whole body skin was peeled off. Thereafter, the subcutaneous fat was removed, and a donut-shaped polyethylene terephthalate film was attached to the outer skin side. The obtained skin piece was attached to a diffusion cell filled with 7 mL of a phosphate buffer heated to 37 ° C., hydrated for 1 hour, and then a prototype tape preparation punched to a diameter of 13 mm was attached to the outer skin side. . After the start of the test, 1 mL of the receptor solution was sampled over time with an autosampler and replenished with the same amount of the test solution. The amount of drug in the collected test solution was quantified by high performance liquid chromatography (HPLC method), and the steady state permeation rate was calculated.

HPLC analysis conditions Detector: Ultraviolet absorptiometer Detection wavelength: 268 nm
Column: Octadecylsilylated silica gel column (5 μm) having an inner diameter of 4.6 mm and a length of 15 cm.
Column temperature: 40 ° C
Mobile phase: 80 mM aqueous ammonium acetate solution adjusted to pH 3.5 / acetonitrile / 2-propanol = 65/30/5

  The steady state permeation rate of trichloromethiazide is shown in Table 1. It was proved that Example 1 was superior in the skin permeability of trichloromethiadi as compared with Comparative Examples 1 to 15 not containing an alkyl glycoside.

Example 2
A transdermal absorption preparation of the present invention was obtained under the same conditions and method as in Example 1 except that the acrylic adhesive base was changed to DURO-TAK (registered trademark) 87-2051.

Example 3
A transdermal absorption preparation of the present invention was obtained under the same conditions and method as in Example 1 except that the acrylic adhesive base was changed to DURO-TAK (registered trademark) 87-2100.

Example 4
A transdermal absorption preparation of the present invention was obtained under the same conditions and method as in Example 1 except that the acrylic adhesive base was changed to GMS (trademark) 1430.

Example 5
The same conditions as in Example 1 except that the acrylic adhesive base was changed to DURO-TAK (registered trademark) 87-2100 to make 3.0 parts by weight of trichloromethiazide and 53.6 parts by weight of the acrylic adhesive base. And a method for obtaining a transdermally absorbable preparation of the present invention.

When the preparations of Examples 2 to 5 were tested in the same manner as in Test Example 1, the steady state permeation rates were 14.0, 14.1, 7.1, and 12.0 μg / cm ² / hr, respectively. It has been confirmed that it has sex.

Comparative Example 16
The transdermally absorbable preparation was prepared under the same conditions and method as in Example 1 except that the acrylic adhesive base was changed to DURO-TAK (registered trademark) 87-9301 which has substantially no carboxyl group or other functional group. Although manufactured, the moldability was not maintained and a percutaneous absorption preparation could not be obtained.

Comparative Example 17
The transdermally absorbable preparation was prepared under the same conditions and method as in Example 1 except that the acrylic adhesive base was changed to DURO-TAK (registered trademark) 87-900A which has substantially no carboxyl group or other functional group. Although manufactured, the moldability was not maintained and a percutaneous absorption preparation could not be obtained.

Example 6
2.0 parts by weight of trichloromethiazide, 2.0 parts by weight of n-octyl-β-D-thioglucopyranoside, 50.0 parts by weight of isopropyl myristate, 0.1 part by weight of aluminum acetylacetonate and an acrylic adhesive base ( A transdermal absorption preparation of the present invention was obtained in the same manner as in Example 1 using 45.9 parts by weight of DURO-TAK (registered trademark) 87-2852) manufactured by National Starch & Chemical Company.

Example 7
2.0 parts by weight of trichloromethiazide, 3.0 parts by weight of n-octyl-β-D-thioglucopyranoside, 50.0 parts by weight of isopropyl myristate, 0.1 part by weight of aluminum acetylacetonate and an acrylic adhesive base ( A transdermal absorption preparation of the present invention was obtained in the same manner as in Example 1 using 44.9 parts by weight of DURO-TAK (registered trademark) 87-2852) manufactured by National Starch & Chemical Company.

Example 8
2.0 parts by weight of trichloromethiazide, 1.0 part by weight of n-octyl-β-D-thioglucopyranoside, 60.0 parts by weight of isopropyl myristate, 0.1 part by weight of aluminum acetylacetonate and an acrylic adhesive base ( A percutaneous absorption preparation of the present invention was obtained in the same manner as in Example 1 using 36.9 parts by weight of DURO-TAK (registered trademark) 87-2852) manufactured by National Starch & Chemical Company.

Example 9
2.0 parts by weight of trichloromethiazide, 2.0 parts by weight of n-octyl-β-D-thioglucopyranoside, 60.0 parts by weight of isopropyl myristate, 0.1 part by weight of aluminum acetylacetonate and an acrylic adhesive base ( A percutaneously absorbable preparation of the present invention was obtained in the same manner as in Example 1 using 35.9 parts by weight of DURO-TAK (registered trademark) 87-2852) manufactured by National Starch & Chemical Company.

Example 10
2.0 parts by weight of trichloromethiazide, 3.0 parts by weight of n-octyl-β-D-thioglucopyranoside, 60.0 parts by weight of isopropyl myristate, 0.1 part by weight of aluminum acetylacetonate and an acrylic adhesive base ( A percutaneously absorbable preparation of the present invention was obtained in the same manner as in Example 1 using 34.9 parts by weight of DURO-TAK (registered trademark) 87-2852) manufactured by National Starch & Chemical Company.

When the formulations of Examples 6 to 10 were tested in the same manner as in Test Example 1, the steady state permeation rates were 7.8, 10.8, 7.0, 11.1, and 16.2 μg / cm ² / hr, respectively. It was confirmed that it has excellent permeability.

Test Example 2 (hairless rat pharmacokinetic study)
The percutaneous absorption preparation (about 12 cm ² ) of Example 1 obtained in the present invention was applied to the back of a 7-week-old HWY male hairless rat, and fixed with gauze and elastopore from above. At 1, 2, 4, 6, 8, 12, and 24 hours after application, blood was collected from the left or right jugular vein, and the plasma trichlormethiazide concentration was measured by LC / MS / MS method.
Separately, trichlormethiazide suspension (suspended in 2% gum arabic solution) was forcibly orally administered to 9-week-old HWY male hairless rats with a gastric sonde. The dose was 0.3 mg / kg. Blood was collected from the left or right jugular vein at 0.5, 1, 1.5, 2, 3, 4, 6, 8, or 10 hours after administration, and the plasma trichlormethiazide concentration was determined by LC / MS / MS method. Measured with

  The results are shown in FIG. 1 (each group n = 3, average value ± standard deviation). As is clear from FIG. 1, when the transdermally absorbable preparation of the present invention is used, the plasma concentration of the thiazide diuretic, which is an active ingredient, is maintained at a constant value for a long time, and there is no transient rapid increase. I understand.

Claims (6)

The following components (A), (B) and (C):
(A) Thiazide diuretics ,
(B) alkylglycoside or alkylthioglycoside,
(C) A matrix-type transdermal preparation containing an acrylic adhesive base containing a copolymer containing a (meth) acrylic acid ester having a carboxyl group in the side chain in the monomer structural unit. Matrix transdermal preparation according to claim 1 Symbol mounting component (A) is a trichlormethiazide. The matrix-type transdermal absorption preparation according to claim 1 or 2, wherein the component (B) is an alkylthioglycoside. Component (B) is a matrix-type transdermal preparation according to any one of claims 1 to 3 is a C ₆ -C ₂₂ alkyl thioglucopyranoside. The matrix type percutaneous absorption preparation according to any one of claims 1 to 4 , wherein the component (B) is n-octyl-β-D-thioglucopyranoside. The component (C) is an acrylic pressure-sensitive adhesive base containing (meth) acrylic acid / (meth) acrylic acid alkyl copolymer or (meth) acrylic acid / (meth) acrylic acid alkyl / vinyl acetate copolymer. The matrix type transdermal absorption preparation of any one of 1-5 .

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