JPH11292762A - Strap containing amine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a strap providing a plaster layer containing a specified ingredient on one side of a support, having better ingredient absorbability than the case with oral administration, good at keeping a drug concentration in blood and useful as a percutaneous preparation for an antiulcerous agent. SOLUTION: This strap is obtained by providing one side of a support with a plaster layer containing (A) preferably 0.5-12 wt.% amine derivative of the formula (R is 4-hydroxyphenyl, 4-carbamoylphenyl or the like) (B) 2-10 wt.% urea and (C) preferably 2.5-15 wt.% polyethylene glycol of the formula HOCH2 (CH2 OCH2 )n CH2 OH [(n) is 2-13] and/or polypropylene glycol. The ingredient A is preferably (±)-(E)-1-[2-hydroxy-2-(4-hydroxyphenyl) ethyl]-3- 2- [5-(methylamino)methyl-2-furyl]methyl}thio}ethyl}-2-(methylsulfonyl) guanidine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to the following general formulas useful as antiulcer agents:

Embedded image The present invention relates to a patch of an amine derivative represented by the formula: wherein R represents a 4-hydroxyphenyl, 4-carbamoylphenyl or 3-methanesulfonylaminophenyl group.

[0002]

BACKGROUND OF THE INVENTION Transdermal preparations can avoid many of the side effects seen in oral preparations. For example, in the case of a drug whose blood concentration exceeding the upper limit of the effective blood concentration causes serious side effects, it is possible to reduce the side effects due to a rapid increase in blood concentration by using a transdermal formulation. . Injectables are also suitable for controlling blood levels, but dosing causes pain in patients. In contrast, transdermal preparations are known to be non-invasive and simple to administer, and to be clearly defined as to whether or not they are administered, so that patients and caregivers can easily control the administration. On the other hand, the amine derivative represented by the general formula [1] described in JP-B-5-43702 is histamine
H ₂ receptor antagonistic action based on improvement of the gastric acid secretion inhibitory action and the gastric mucosal blood flow and mucus glycoprotein amount based on combines protective factor enhancing action, in particular, (±) - (E) -1- [2- hydroxy -
2- (4-hydroxyphenyl) ethyl] -3- [2-
[[[5- (Methylamino) methyl-2-furyl] methyl] thio] ethyl] -2- (methylsulfonyl) guanidine; also known as (±)-(E) -3- [2-hydroxy-2- ( 4-hydroxyphenyl) ethyl] -1- [2- [5- (methylaminomethyl) furfurylthio] ethyl] -2-methylsulfonylguanidine or (±)-(E) -N-[[2-hydroxy-2- (4-hydroxyphenyl) ethylamino]-
[2- [5- (Methylaminomethyl) furfurylthio] ethylamino] methylene] methanesulfonamide is useful as an anti-ulcer agent. However, its transdermal formulation is not known.

[0003]

SUMMARY OF THE INVENTION As a preparation which can administer the amine derivative represented by the general formula [1] in a non-invasive and safe manner, and which can easily control the administration by the patient himself, There is a need for a technology for transdermal preparations. However, since the skin has a barrier function to prevent foreign substances from entering the body from the outside world, even if a drug is administered by a transdermal formulation, a sufficient amount of the drug to exhibit a pharmacological effect enters the systemic circulation. Absorption is not always easy. Furthermore, it is known that the barrier function of the stratum corneum increases with aging (aging and skin,
53, 1994, Kinbara Publishing), it is difficult to percutaneously absorb a sufficient amount of a drug to show its efficacy in middle-aged and elderly patients to whom this drug is administered. In addition, the skin permeability of a drug depends on the intrinsic physicochemical properties of the drug, and is closely related to the interaction between the drug, the base, and the skin. Development of Transdermal and Transmucosal Absorbents and New Tests, Experiments, and Evaluation Methods,
Page, 1986, Techno Eye Publishing Department). An object of the present invention is to provide an amine derivative represented by the general formula [1] exhibiting good transdermal absorbability, in particular, (±)-(E) -1- [2-hydroxy-2-
(4-hydroxyphenyl) ethyl] -3- [2-[[[5-
This is the development of a patch of (methylamino) methyl-2-furyl] methyl] thio] ethyl] -2- (methylsulfonyl) guanidine.

[0004]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventor has found that the oral administration of an amine derivative represented by the general formula [1] can be achieved by using it as a patch. Found that higher absorption could be obtained,
The inventor has found that by adding urea and polyethylene glycol and / or polypropylene glycol to the patch, a patch whose transdermal absorbability is further improved can be obtained, and the present invention has been completed.

Hereinafter, the present invention will be described in detail. As the amine derivative represented by the general formula [1] used in the patch of the present invention, any of an optically active compound and a racemic compound can be used. Also, any of the other isomers (eg, geometric isomers and tautomers), solvates, hydrates, and crystals of various shapes can be used.

The general formula [1] used for the patch of the present invention
Can be produced by the method described in Japanese Patent Publication No. 43702/1993, or the like. The amount of the amine derivative represented by the general formula [1] used in the patch of the present invention is preferably 0.1 to 20% by weight, more preferably 0.5 to 12% by weight.

The polyethylene glycol used in the patch of the present invention is a compound represented by the following formula: HOCH ₂ (CH ₂ OCH ₂ ) _n CH ₂ OH (n is an integer of _{2 to} 13). Specific examples include, for example, triethylene glycol, tetraethylene glycol, polyethylene glycol 200, polyethylene glycol 30
0, polyethylene glycol 400, polyethylene glycol 600, etc., among which triethylene glycol and tetraethylene glycol are particularly preferred. Also,
Examples of the polypropylene glycol include compounds represented by the following formula H {OCH (CH ₃ ) CH ₂ } mOH (m is an integer of 2 to 10). Specifically, for example, dipropylene glycol And tripropylene glycol. Further, a mixture of polyethylene glycol and polypropylene glycol may be used. The blending amount of polyethylene glycol and / or polypropylene glycol used in the patch of the present invention is preferably 1 to 20% by weight, more preferably 2.5 to 15% by weight.

The amount of urea used in the patch of the present invention is preferably 0.5 to 20% by weight, more preferably 2 to 10% by weight.
% By weight.

[0009] The patch of the present invention may optionally contain a nitrogen-containing polymer coating agent. The nitrogen-containing polymer coating agent that can be added to the patch of the present invention as necessary includes a (meth) acrylate ester containing no nitrogen in the ester residue and a (meth) acrylate ester containing nitrogen in the ester residue. Is preferred. Examples of the ester residue of a (meth) acrylate ester containing no nitrogen in the ester residue include straight-chain or branched C-substitutes which may be substituted with one or two hydroxyl groups.
_Examples of the alkyl group include 1 to ₁₂ alkyl groups, and preferred groups include a methyl group, an ethyl group, a 2-hydroxyethyl group, a butyl group, a hexyl group, an octyl group, a 2-ethylhexyl group, a decyl group, and a lauryl group. Among them, a methyl group, an ethyl group and a butyl group are particularly preferred.

The ester residue of a (meth) acrylate ester containing nitrogen in the ester residue includes C
_1-8 include alkylamino ethyl group or _{C 1-8} alkyl ammonio ethyl _group, the _{C 1-8} alkyl groups _{C 1-8} alkylamino ethyl and _{C 1-8} alkyl ammonio ethyl group, a methyl group , An ethyl group, a propyl group, a butyl group, a hexyl group, an octyl group and a 2-ethylhexyl group, and a methyl group is particularly preferable. More specifically, examples include dimethylaminoethyl, dimethylammonioethyl and trimethylammonioethyl groups.

Preferable specific examples of the nitrogen-containing polymer coating agent include methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (trade name: Eudragit E100: manufactured by Laem Pharma), acrylic acid Ethyl / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer (trade name: Eudragit RS30D: manufactured by Laem Pharma Co., Ltd.). The amount of the nitrogen-containing polymer coating agent used in the patch of the present invention is preferably 0.5 to 2
0% by weight, more preferably 1 to 10% by weight.

The patch of the present invention may further contain, if necessary, a plasticizer, a skin irritation reducing agent, a pH adjuster, an absorption promoter and the like. Glycerin and the like as plasticizers and skin irritation reducing agents, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, sodium hydroxide, diisopropanolamine and diethanolamine as pH adjusters, oleyl alcohol as an absorption enhancer, And diethyl sebacate.

The base used for the patch of the present invention includes, for example, an acrylic pressure-sensitive adhesive. As the acrylic pressure-sensitive adhesive, a homopolymer of (meth) acrylic acid ester or (meth) acrylic acid; a mixture of (meth) acrylic acid ester and (meth) acrylic acid, (meth) acrylic acid ester or (meth) acrylic acid Copolymers of acids;
And copolymers of the above monomers with one or more other polymerizable monomers, except those containing nitrogen as an ester residue of (meth) acrylate.

Examples of the polymerizable monomer include vinyl acetate, and examples of the acrylic pressure-sensitive adhesive include a methyl acrylate / acrylate-2-ethylhexyl copolymer resin emulsion (trade name: Nicazole TS-620: manufactured by Nippon Carbide Co., Ltd.). ), Methacrylic acid / n-butyl acrylate copolymer (trade name: Primal N-580NF: manufactured by Rohm and Haas Japan), ethyl acrylate / methyl methacrylate copolymer emulsion (trade name: Eudragit NE30D: Lame) Pharma Co., Ltd.) or a mixture thereof.

The support for the patch of the present invention is not particularly limited as long as it is drug-impermeable and can form and support a plaster layer. Examples of the support include polyethylene, polypropylene, polyester, polyvinyl acetate, and the like. Ethylene / vinyl acetate copolymer, polyvinyl chloride, polyurethane, nylon, aluminum and the like can be used. These materials are used as a single layer film or a laminated film. The thickness of the support is preferably 5 to 500 µm, more preferably 5 to 200 µm.

The patch of the present invention has a release paper on the sticking surface to protect the surface of the plaster layer until use. The release paper is not particularly limited, but polyethylene terephthalate or paper subjected to a release treatment with a silicone resin or the like is used.

The patch of the present invention can be produced by a method usually used in the art, and the method for producing the plaster solution may be, for example, polyethylene glycol, a compound represented by the general formula [1]. Is added, and urea is further added, followed by uniform stirring. After that, there is a method of adding an emulsion of the base material and stirring.

In each step of the production method, the pH can be adjusted by appropriately adding a pH adjuster.

When a nitrogen-containing polymer coating agent is blended if necessary, the method for producing the plaster solution includes, for example, (1) pulverizing the nitrogen-containing polymer coating agent, and then removing the base emulsion. Addition method (2) Method of mixing aqueous dispersion of nitrogen-containing polymer coating agent and base emulsion (3) Dissolution of nitrogen-containing polymer coating agent with acid and addition of base emulsion There is a way to do.

In the case of the method (1), after the ground nitrogen-containing polymer coating agent is dispersed in polyethylene glycol, an aqueous solution of the compound represented by the general formula [1] is added, and urea is further added thereto to form a uniform solution. And stir. Thereafter, the base emulsion is added and stirred. In the case of the method (2), an aqueous solution of the compound represented by the general formula [1] is added to an aqueous dispersion of a nitrogen-containing polymer coating agent, and polyethylene glycol and urea are further added and uniformly stirred. Thereafter, the base emulsion is added and stirred. In the case of the method (3), the nitrogen-containing polymer coating agent and the acid are heated in an aqueous solution to form a uniform solution. An aqueous solution of the compound represented by the general formula [1] is added to the obtained solution, and polyethylene glycol and urea are further added and uniformly stirred. Thereafter, the base emulsion is added and stirred.

Examples of the acid used in the method (3) include acetic acid, caprylic acid, capric acid, lauric acid, oleic acid, succinic acid, adipic acid, suberic acid, sebacic acid, lactic acid, gluconic acid, and apple. include hydrochloric acid, sulfuric acid, of one or more of inorganic acids such as phosphoric acid combination; acid, mono C _2-22, such as tartaric acid and citric acid - -, di, organic acids such as tricarboxylic acid However, capric acid, lauric acid, adipic acid, lactic acid and hydrochloric acid are preferred. The amount of the acid used is 0.
8 to 2.0 times equivalent.

The plaster solution obtained by mixing the respective ingredients in the above-mentioned manner is applied to a support, dried and then pasted on a release paper, or the plaster solution is applied on a release paper and dried, and then obtained. A patch can be produced by bringing the plaster layer into close contact with the support.

[0023]

EXAMPLES Next, the present invention will be described with reference to examples, but the present invention is not limited to these examples. In Examples, as the amine derivative represented by the general formula [1],
(±)-(E) -1- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] -3- [2-[[[5- (methylamino)
Methyl-2-furyl] methyl] thio] ethyl] -2- (methylsulfonyl) guanidine [hereinafter referred to as compound A. ] Was used.

Example 1 200 ml of an aqueous solution containing 200 mg of compound A and adjusted to pH 6 using 1 mol / L hydrochloric acid was added to 200 mg of triethylene glycol, and 1 ml of water and 100 mg of urea were further added and stirred uniformly. Thereafter, a methyl acrylate / ethyl-2-ethylhexyl acrylate copolymer resin emulsion (trade name: Nicazole TS-) was adjusted to pH 6 using 1 mol / L sodium hydroxide.
620; solid content 57-61% (W / W): manufactured by Nippon Carbide) 2.6
5 g was added, and the mixture was stirred at room temperature for 1 hour, further adjusted to pH 6 using 1 mol / L sodium hydroxide, and stirred at room temperature for 20 minutes to obtain a plaster solution. The resulting plaster solution was uniformly coated on a polyester support so that the content of Compound A was 10 mg / 10 cm ² / plast 100 mg, air-dried overnight, and then subjected to a release treatment with a silicone resin made of polyethylene terephthalate. Was adhered to obtain a patch.

Example 2 3 ml of an aqueous solution containing 300 mg of compound A and adjusted to pH 4 using 1 mol / L hydrochloric acid was added to 300 mg of triethylene glycol, and 1.5 ml of water and 150 mg of urea were further added and uniformly stirred. . Thereafter, 3.68 g of Nicazole TS-620 adjusted to pH 4 using 1 mol / L sodium hydroxide was added, and the mixture was stirred at room temperature for 45 minutes.
The mixture was stirred at room temperature for 1.5 hours to obtain a plaster solution. Thereafter, a patch was obtained by the same operation as in Example 1.

Example 3 Methyl methacrylate / pulverized to 200 mg of triethylene glycol using a pneumatic pulverizer to a particle diameter of 20 μm or less.
Butyl methacrylate / dimethylaminoethyl methacrylate copolymer (trade name: Eudragit E100:
After dispersing 60 mg of Compound A, 200 mg of Compound A
Was added, and 2 ml of an aqueous solution adjusted to pH 4 using 1 mol / L hydrochloric acid was added. Further, 1 ml of water and 100 mg of urea were added, and the mixture was stirred uniformly. Then, using 1 mol / L sodium hydroxide, pH4
2.44 g of Nicazole TS-620 was added at room temperature to obtain 1
The mixture was stirred for 1 hour, further adjusted to pH 4 using 1N hydrochloric acid, and stirred at room temperature for 1 hour to obtain a plaster solution. Thereafter, a patch was obtained by the same operation as in Example 1.

Example 4 Eudragit E100 pulverized to 300 mg of triethylene glycol using an air-flow pulverizer to a particle diameter of 20 μm or less.
After dispersing 90 mg, water 1.5 ml, urea 150 mg, Nicazole TS-
3.46 g of 620 were added and the mixture was stirred at room temperature for 1 hour. afterwards,
3 ml of an aqueous solution containing 300 mg of compound A and adjusted to pH 4 using 1 mol / L hydrochloric acid was added, and p was further added using 1 mol / L hydrochloric acid.
The mixture was changed to H4 and stirred at room temperature for 1 hour to obtain a plaster solution. Thereafter, a patch was obtained by the same operation as in Example 1.

Reference Example 3 ml of an aqueous solution containing 300 mg of compound A and adjusted to pH 4 using 1 mol / L hydrochloric acid, and adjusted to pH 4 using 1 mol / L sodium hydroxide.
4.41 g of Nicazole TS-620 and 1.5 ml of water were mixed and stirred at room temperature for 40 minutes. Further, the mixture was adjusted to pH 4 with 1 mol / L sodium hydroxide and stirred at room temperature for 1.5 hours to obtain a plaster solution. Thereafter, a patch was obtained by the same operation as in Example 1. Next, the effects of the patch of the present invention will be described.

Percutaneous absorption test in rats Rats (Wistar, male, body weight 200
250250 g) of the back was removed with a hair clipper and a depilatory cream (trade name: Deveil Depilatory Cream: Shiseido), and the patch (compound A content of 10) obtained in Example 2 and Reference Example was removed.
mg / a 10cm ^{2 /} plaster 100mg) was administered to the back. As a control, an aqueous solution containing 10 mg of compound A was orally administered. Blood is collected from the jugular vein with time, plasma is separated, and pre-treated column B
on Elut CBA (Varian) and YM
Using C Dispo SPE C18 (manufactured by YMC),
Compound A was extracted from plasma, and the blood concentration was measured by high performance liquid chromatography. The area under the blood concentration-time curve (AUC _0-4 ) of each sample is shown in Table 1.

[0030]

[Table 1]

[0031]

EFFECT OF THE INVENTION A plaster layer containing (a) an amine derivative represented by the general formula [1]; (b) urea; (c) polyethylene glycol and / or polypropylene glycol on one surface of the support of the present invention. The patch provided with is provided with an absorbability higher than that of oral administration, and is excellent in persistence in blood concentration, and is useful as a transdermal preparation of an antiulcer agent.

Claims (4)

[Claims] 1. A patch comprising a support and a plaster layer containing the following components (a) to (c) provided on one surface of the support. (A) General formula (Wherein R represents a 4-hydroxyphenyl, 4-carbamoylphenyl or 3-methanesulfonylaminophenyl group). (B) Urea (c) Polyethylene glycol and / or polypropylene glycol 2. The patch according to claim 1, wherein R is a 4-hydroxyphenyl group in the amine derivative represented by the general formula [1] of the component (a). 3. The patch according to claim 1, wherein the component (c) is polyethylene glycol. 4. Component (c) has the formula HOCH ₂ (CH ₂ OCH ₂ ) _n C
The patch according to any one of claims 1 to 3, wherein the patch is polyethylene glycol represented by H2OH (n is an integer of _{2 to} 13).