JPH08245377A - Pharmaceutical preparation for percutaneous absorption - Google Patents

Abstract

PURPOSE: To obtain the subject pharmaceutical preparation, having strong and selective blocking actions on α1 receptors and useful for improving dysuria, lower uropathy, etc., and containing a tamuslosin free base. CONSTITUTION: This pharmaceutical preparation for percutaneous absorption contains tamuslosin free base of the formula. The pharmaceutical preparation preferably further contains an acrylic or a silicone-based tacky agent and further a percutaneous absorbefacient and/or a dissolvent. The acrylic tacky agent is preferably, e.g., a polyaminoacrylate, containing a fatty acid added thereto and comprising a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, lauric acid, adipic acid, glycerol, aqueous hydrogen peroxide and water and the percutaneous absorbefacient is preferably a higher fatty acid ester, e.g., isopropyl myristate and/or a higher fatty acid, e.g., capric acid. The dissolvent is preferably glycols, e.g., propylene glycol, ethyl citrate, etc.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION

[0002]

Embedded image

A percutaneously absorbable preparation characterized by containing a tamsulosin free base represented by:
The present invention relates to a transdermal absorption preparation for blocking a receptor.

Further, the percutaneous absorption preparation of the present invention contains an acrylic adhesive or a silicone adhesive in order to achieve effective and safe transdermal tamsulosin delivery. Alternatively, it is characterized by containing a dissolving agent, and is preferably provided as a tape, patch or matrix agent.

The transdermal preparation of the present invention is specifically α1.
It is used as a receptor-blocking percutaneous absorption preparation for the purpose of improving urinary difficulty and lower urinary tract diseases.

The present invention also has the following formula

[0007]

[Chemical 6]

[0008] The present invention relates to an α1 receptor blocker characterized by containing a tamsulosin free base, preferably an α1 receptor blocker for transdermal absorption.

The α1 receptor blocker of the present invention is specifically used as an α1 receptor blocker for transdermal absorption for the purpose of improving urination difficulty, lower urinary tract diseases and the like.

[0010]

[Prior Art] The following formula

[0011]

[Chemical 7]

5- [2- [2- (2-ethoxyphenoxy) ethylamino] -2-methylethyl]-
2-Methoxybenzenesulfonamide is called tamsulosin and has a strong and selective α1 receptor blocking action (Japanese Patent Laid-Open No. 56-110665). Its α1-receptor blocking action is stronger than that of brazosin hydrochloride, and exhibits a pharmacological action of ameliorating the contractions of the rabbit prostate, urethra and bladder trigone and human urethra and bladder trigone. Therefore, it can be clinically used as an ameliorating agent for urinary difficulty, lower urinary tract diseases, etc., but such diseases are often found in the elderly, and oral preparations or percutaneous absorption (or cutaneous absorption) that act for a long time are effective. Development of sustained-release preparations such as permeation) preparations has been desired.

In particular, the elderly or bedridden elderly are often patients with pathological conditions that are difficult to administer orally. Therefore, development of a transdermal absorption agent that can be administered more easily than oral preparations is desired. In addition, transdermal preparations are strongly developed from this aspect as well because they do not suffer from the first-pass effect that accompanies oral preparations, the drug effect lasts for a long time, and the administration can be discontinued. Is desired.

However, the skin permeability of drugs is generally low,
Only certain limited drugs such as nitroglycerin and scopolamine have been used as transdermal preparations.

Human epidermal tissue has a barrier function of preventing the invasion of foreign substances, and the transdermal absorption of a drug is often determined by the interaction among the drug, base and skin. Are known. Therefore, although the design of a transdermal preparation is achieved by solving various problems relating to the transdermal absorption of a drug used, in particular, increasing the drug permeation rate in the stratum corneum permeation process, which is the rate-determining step of transdermal absorption, It is important to put together a safe system with less skin irritation without deteriorating the increased transdermal permeability of the drug in order to exert an accurate drug effect. Under such technical background, research has been promoted on various transdermal absorption enhancers.

The percutaneous absorption enhancer covers a wide range from organic solvents such as ethanol and propylene glycol to surfactants, but compounds having a long hydrocarbon such as laurocapram and a relatively large ring (for example, US Pat. No. 398).
9816), fatty acids, dimethyl sulfoxide, pyrrolidones, terpenes (Drug Design and Delivery, 4 ,
313 (1989)) and the like are known. In addition, ethanol (for example, US Pat. No. 4,379,454), glycerol monolaurate (for example, US Pat. No. 4,746,515).
No.), polyethylene glycol monolaurate (for example, US Pat. No. 4,568,343), and propylene glycol monolaurate (for example, Japanese Patent Publication No. 4-505157). Among them, regarding fatty acids, it has been reported that the unsaturated side chains have a greater promoting effect than the saturated ones (H.Okamoto et al., Chem. Pharm. Bull., 35 , 4605-4).
608 (1987)) and its effect is reported to be maximum when the carbon number is 12 (lauric acid) (T.Ogis).
o et al., J. Pharm. Sci., 79 , 1065-1071 (1990)).
However, similar transdermal absorption promoting effects are not observed with all drugs, and a base and a percutaneous absorption promoting agent (both combinations are possible) depending on the physicochemical properties of the drug. It is necessary to select. In addition, the selection and combination cannot be easily predicted from well-known facts, and many trys are generally used.
And error must be repeated. Further, if the selection is wrong, not only the effect of promoting percutaneous absorption is impaired but also strong skin irritation may be observed.

On the other hand, regarding the transdermal absorption preparation for blocking α1 receptors, a transdermal composition for administering planzosin is disclosed in Japanese Patent Publication No. 6-510290, but prazosin-free instead of prazosin hydrochloride is disclosed. The use of a base does not improve its transdermal absorbability, and it is further stated that addition of an absorption enhancer is essential to achieve effective transdermal prazosin delivery in humans. There is no mention of tamsulosin free bass.
A transdermal pharmaceutical preparation for administering alfuzosin is described in JP-A-6-157315.
There is no description of tamsulosin free base, nor is there any data on the transdermal absorbability of alfuzosin.

The present inventors previously prepared a transdermal preparation of tamsulosin hydrochloride and applied for a patent (Japanese Patent Laid-Open No. 3-1738).
16, international publication number WO94 / 16682). However, in the above-mentioned technique, it is necessary to use several types of percutaneous absorption enhancers having a strong action for promoting percutaneous absorption and to prepare an optimum dosage form.

[0019]

Therefore, it has been an important subject to create a pharmaceutical technology capable of achieving transdermal tamsulosin delivery that is effective and highly safe with an industrially simpler formulation or dosage form.

[0020]

The inventors of the present invention further investigated an α1 receptor blocker for transdermal absorption and found that when tamsulosin free base was used in place of tamsulosin hydrochloride, the drug was unexpectedly found. They found that their own transdermal absorbability was significantly improved, and a percutaneous absorption preparation using a certain more moderate percutaneous absorption enhancer, dissolution agent, and pressure-sensitive adhesive gave a good transdermal absorption effect. The inventors have found that they have been achieved and have completed the present invention.

The present invention will be described in detail below.

The transdermal therapeutic preparation according to the present invention is most preferably a patch as a preparation form of a transdermal therapeutic system (TTS), but it is highly safe and has excellent transdermal absorption promoting effect. It may be a conventional patch, an ointment including a gel ointment, a transdermal preparation such as an emulsion or a liquid, which has utility as an applied preparation.

The patch as a preparation form of TTS usually comprises a support and a pressure-sensitive adhesive layer capable of releasing the drug (when the drug is mixed in the pressure-sensitive adhesive layer, when the drug layer and the pressure-sensitive adhesive layer are separated, In some cases, it may include a drug release part of various forms),
And a release film that protects this adhesive layer.

For simplicity, the patch of the drug-mixed adhesive layer will be explained. The adhesive layer contains a drug, a pharmaceutically acceptable conventional transdermal absorption enhancer and other patch bases. Mix with and make a plaster.

The patch base is capable of uniformly mixing or dispersing the drug, releases the drug when applied, and is stable over time without impairing the transdermal absorption of the drug promoted by the composition of the present invention. Any base that can be put together as a system,
Included are all general-purpose patch bases other than those that diminish the action of the composition of the present invention.

Specific examples of the adhesive component include natural rubber,
Styrene-butadiene rubber (SBR), polyisoprene rubber, polyisobutylene rubber, styrene-isoprene-
Acrylics such as styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), silicone rubber (organopolysiloxane rubber), (meth) acrylic acid- (meth) acrylic acid ester copolymer Natural or synthetic rubbers such as copolymers, super absorbent polymers such as starch acrylate, sodium polyacrylate carboxymethyl cellulose (CMC),
Carboxymethyl cellulose sodium (CMCN
a), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), methyl vinyl ether maleic anhydride copolymer, sodium alginate, propylene glycol alginate ester, pectin, xanthan gum,
Xanthan gum, locust bean gum, guar gum,
Examples thereof include hydrophilic polymers such as arabic galactan and sodium hyaluronate.

Rubber and the like can be used as a latex emulsion. Further, these adhesive components, superabsorbent polymers and hydrophilic polymers can be used in appropriate combination.

Components added to these as necessary include mudifying agents such as gelatin; powdered excipients such as kaolin, bentonite, zinc oxide, titanium oxide, calcium chloride and zinc chloride; Quinton (trade name, Nippon Zeon Company), petroleum resins such as Alcon (trade name, Arakawa Chemical Co., Ltd.), tackifying components such as resins such as rosin, hydrogenated rosin, ester gum; higher fatty acid esters such as polybutene, liquid paraffin, and isopropyl myristate, silicone. Softeners for oils and various vegetable oils; glyceryl fatty acid esters such as glyceryl monostearate, polyoxyethylene sorbitan monolaurate (eg Nikko Chemicals: TL-10), polyoxyethylene sorbitan monostearate (eg Nikko Chemicals: TS-1
0) and other polyoxyethylene sorbitan fatty acid esters, sorbitan monostearate (Nikko Chemicals:
Sorbitan fatty acid ester such as SS-10), HCO
A surfactant such as polyoxyethylene hydrogenated castor oil such as -60 (for example, Nikko Chemicals); methylparaben,
Ethylparaben, propylparaben, butylparaben,
Sorbic acid, salts of sorbic acid, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BH)
T), preservatives or antioxidants such as nordihydroguaiaretic acid, guaiacol esters, etc .; pH adjusting agents for organic acids such as acetic acid, succinic acid, citric acid, malic acid, fumaric acid, maleic acid, tartaric acid ( It also has useful properties as a patch base itself; absorption agents such as salts that generate trivalent metal ions such as aluminum chloride, aluminum sulfate, alum and aluminum allantoinate: moisturizers such as alkaline earth metal salts. A flavoring agent, a solvent for a drug, water and the like.

In the percutaneous absorption preparation of the present invention, higher fatty acid esters and higher fatty acids are preferable as the percutaneous absorption promoter, and of course, these percutaneous absorption promoters may contain one kind or two or more kinds. Is.

The higher fatty acid has, for example, 6 to 3 carbon atoms.
2 saturated or unsaturated fatty acids, specifically, for example, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecyl acid, lauric acid, tridecyl acid, myristic acid, pentadecyl acid, valmitic acid,
Examples include heptadecyl acid, stearic acid, oleic acid, nonadecanoic acid, arachidic acid, linoleic acid, linolenic acid, behenic acid, lignoceric acid, cerotic acid, heptacosanoic acid, montanic acid, melissic acid, laxellic acid, elaidic acid, and brassic acid. To be Of these, capric acid, lauric acid, myristic acid, oleic acid and the like are preferable. Of these, capric acid and lauric acid are particularly preferable.
Examples of the higher fatty acid ester include (A) ester of higher fatty acid and alcohol, (B) ester of saturated or unsaturated fatty acid having 10 to 22 carbon atoms and glycerin, or hydrogenated products thereof. For example, as (A), myristyl palmitate, stearyl stearate, myristyl myristate, ceryl lignocerate, lacceryl cerotate, lacceryl laxerate,
Fatty acid esters such as isopropyl myristate, diethyl sebacate, diisopropyl adipate and isopropyl palmitate, natural waxes of animal origin such as lanolin, beeswax, spermaceti and shellac wax, natural waxes of plant origin such as carnauba wax and candelilla wax can give. More preferably, myristyl myristate, isopropyl myristate, diethyl sebacate, diisopropyl adipate,
Examples include isopropyl palmitate.

As (B), glyceryl monolaurate, glyceryl monomyristate, glyceryl monostearate, glyceryl monooleate, glyceryl dilaurate, glyceryl dimyristate, glyceryl distearate, glyceryl trilaurate, glyceryl trimyristate, Examples thereof include glyceryl tristearate. Of these, glyceryl monolaurate, glyceryl monomyristate, glyceryl monooleate, and glyceryl monostearate are preferable. Examples of the vegetable oil include castor oil, olive oil, sesame oil, gents oil, safflower oil, cottonseed oil, turpentine oil, and vegetable oils and fats hydrogenated to these. Of these, castor oil, olive oil, cottonseed oil and the like are preferable. Furthermore, mink oil, egg yolk oil, animal oils such as squalane and squalene, lanolin and its derivatives can also be suitably used as the ointment base. These bases may be used as a mixture of one or more kinds.

The amount of the absorption enhancer to be blended varies slightly depending on the base and dosage form used, but in the present invention, it is generally about 0.1 to 50%, preferably about 0.1 to 30%, especially about It is preferably blended so as to be 0.5 to 10%.

Examples of the solubilizer used in the percutaneous absorption preparation of the present invention include glycols, fatty acids, triethyl citrate and triacetin.

As glycols, ethylene glycol, propylene glycol, triethylene glycol,
Examples thereof include 1,3-butylene glycol and polyethylene glycol, with propylene glycol, polyethylene glycol and 1,3-butylene glycol being preferred.
Also, a base containing polyethylene glycol as a main component, for example, a mixture of a low polymerization degree polyethylene glycol such as Macrogol 400 and a high polymerization degree polyethylene glycol such as Macrogol 4000 in an appropriate ratio is preferably used. You can

The fatty acids defined here have 5 to 2 carbon atoms.
0 chain carboxylic acid, the carbon chain is saturated, unsaturated,
It may be linear or branched, may be substituted, and is used alone or in combination. Examples thereof include valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, linoleic acid, linoleic acid, arachidonic acid and adipic acid. Of these, capric acid, lauric acid, myristic acid, oleic acid and the like are preferable. Of these, capric acid and lauric acid are particularly preferable.

The amount of the solubilizer blended may be an amount that does not impair the moldability of the preparation, but is preferably in the range of 1 to 50% by weight.

The amounts of these bases including adhesives, percutaneous absorption enhancers, solubilizers, etc. are the same as the amounts of the usual percutaneous absorption enhancers used in medicine and pharmaceutically, and the types of bases. Although it is determined in consideration of the action and effect of the present invention, it is about 30 to 97% by weight, preferably 60 to
It is 92% by weight. It goes without saying that the type and amount of the base used in a hydrous patch such as a poultice and a patch such as a tape are very different.

In order to produce the percutaneous absorption preparation of the present invention, the components of the drug, the usual pharmaceutically acceptable percutaneous absorption enhancer, and other bases are uniformly kneaded, and the kneaded product is supported. Spread on the body, if necessary dry or attach a holding film to the support and then attach a release film, cut into an appropriate size,
To wrap.

Taking into consideration the physicochemical properties of each component of the drug, the base and the percutaneous absorption enhancing composition used for facilitating the preparation of a uniform plaster, the order of addition and kneading is appropriately set,
Alternatively, heating and ultrasonic treatment are free.

When a poultice or tape preparation is produced by the emulsion method, the rubber and the like as an adhesive component can be prepared in advance as a latex emulsion and added and kneaded.

The spreading is carried out according to a conventional method such that the produced plaster is held on a support or a release film at an appropriate temperature or heated to evenly apply it to a prescribed thickness. Drying is performed when a tape preparation or the like having a low water content is produced by a solvent method or an emulsion method, and the solvent or water is volatilized.

Next, when the plaster is spread on a support, a release film is stuck on the plaster, and when the plaster is spread on the release film, the support is stuck on the spread plaster.

As the support, cloth, non-woven fabric, plastic film, aluminum foil, aluminum laminated plastic film and the like are used. Further, as the release film, a plastic film such as cellophane or polyester film subjected to a release treatment and a paper coated with a release agent such as silicon are preferably used.

As the retaining film, a porous film or a solvent permeable film is used, and preferably a porous plastic film, an ethylene-vinyl acetate copolymer film or an ethylene-vinyl alcohol copolymer film is used. To be

Other external preparations such as ointments based on macrogol and the like, gel agents based on carboxyvinyl polymer (hydrogel or hydrophilic gel ointment), emulsions based on water, oily ingredients and emulsifiers A liquid preparation and a liquid preparation can also be formulated according to a conventional method.

For example, the liquid preparation is obtained by adding a solvent to a relatively high drug, an ordinary pharmaceutically acceptable percutaneous absorption enhancer, and optionally other drugs or bases. Dissolve in, and pour this into a liquid agent container for external use in a predetermined amount and package.

The percutaneous absorption preparation of the present invention can be provided as it is, but in addition to the above-mentioned essential components, a fragrance, a stabilizer, a moisturizing agent, an antioxidant, a pH adjusting agent, and an increasing agent may be added if necessary. To prepare external preparations such as patches, tapes, poultices, ointments, lotions, solutions, liniments, impregnants, gels, and matrix agents by adding known ingredients that are acceptable in the formulation such as sticky agents, etc. Of these, patches, tapes, matrix agents and the like are preferable. A tape agent that can be produced by a particularly simple process is preferable, and in this case, an adhesive agent that contains an acrylic adhesive agent or a silicone adhesive agent and, if desired, a percutaneous absorption enhancer and / or a dissolving agent is preferable. .

Examples of the pressure-sensitive adhesive used when the percutaneous absorption preparation of the present invention is used as a tape preparation include an acrylic pressure-sensitive adhesive and a silicon-based pressure-sensitive adhesive. Acrylic pressure-sensitive adhesive is a general term for pressure-sensitive adhesives produced by polymerizing one or more acrylic acid ester or methacrylic acid ester, and is generally a low glass transition point monomer (butyl acrylate, acrylic acid-2) which is an adhesive component. -Ethylhexyl, etc.), a high glass transition point monomer (vinyl acetate, methyl methacrylate, etc.) that is an aggregation component, and an unsaturated carboxylic acid, which is a modifying component, are the main components.

Acrylic pressure-sensitive adhesives composed of acrylic acid esters are roughly classified into solvent types polymerized in an organic solvent such as toluene and ethyl acetate, and emulsion types emulsion-polymerized in an aqueous solution.

The low glass transition point monomer used in the acrylic pressure-sensitive adhesive composed of acrylic acid ester is
Ethyl acrylate, butyl acrylate, acrylic acid 2-
Examples include ethylhexyl and isononyl acrylate.
Examples of the high glass transition point monomer include vinyl acetate, acrylonitrile, acrylamide, styrene, methyl methacrylate, and methyl acrylate, and the modifying components include methacrylic acid, acrylic acid, itaconic acid, maleic anhydride, and methacrylic acid. Hydroxyethyl acid, hydroxypropyl methacrylate, dimethylaminoethyl methacrylate, acrylamide, methylol acrylamide,
Glycidyl methacrylate and the like can be mentioned, and the acrylic pressure-sensitive adhesive comprising an acrylic acid ester used in the present invention is optionally and combination polymerized.

Specifically, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion (generic name; trade name; Nicazole TS-620, manufactured by Nippon Carbide Industries Co., Ltd.) methacrylic acid / n-butyl acrylate copolymer ( General name; trade name; Primal N-580NF, manufactured by Rohm & Haas) and the like.

The acrylic pressure-sensitive adhesive composed of methacrylic acid ester is generally produced by dissolving a methacrylic acid ester copolymer in an aqueous solution at a high concentration, and the methacrylic acid copolymer to be used is , Methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (generic name; trade name; Eudragit E100, manufactured by Rohm & Pharma), methacrylic acid / methyl methacrylate copolymer, and the like.

As a specific example, plastoid E (trade name, manufactured by Rohm & Pharma Co., general name: fatty acid-containing polya
minoacrylate aqueous solution), Plastoid L (trade name, manufactured by Rohm & Pharma, general name: anionic poly (meth))
Acrylate aqueous solution). Further, there is an adhesive composed of Eudragit E100, capric acid, adipic acid, glycerin, hydrogen peroxide solution and water. Adhesion ratio of 15.9: 9.2: 1.8: 1: 0.1: 79 Agents are preferred.

Another adhesive used when the percutaneous absorption preparation of the present invention is used as a tape preparation is a silicone adhesive. The silicone-based adhesive is a derivative of polysiloxane (silicon polymer such as polydimethylsiloxane and amine-resistant polydimethylsiloxane), and specifically, BIO-PSA X7-450.
1, X7-4201 (trade name, manufactured by Dow Corning) and the like. If necessary, 360
Silicone oil such as MEDICAL FLUID (trade name, manufactured by Dow Corning) can be added.

The content of the drug is usually 0.5 to 0.5 in the adhesive layer.
40% by weight, preferably about 1 to 30% by weight.

The content of the adhesive is 50-98.
It is 5% by weight, preferably 55 to 95%.

[0057]

[Examples] The following examples are given to describe the method for producing the percutaneous absorption preparation of the present invention in more detail.

Example 1 0.5 parts by weight of tamsulosin free base (hereinafter referred to as "part"), 49.75 parts of ethanol and 49.75 of purified water.
A part was taken and mixed and dissolved.

Example 2 0.5 parts tamsulosin free base, ethanol 47.
5 parts, purified water 47 parts and diethyl sebacate (DE
S) 5 parts was taken and mixed and dissolved.

Example 3 5 parts of tamsulosin free base, 85 parts of propylene glycol (PG) and 10 parts of capric acid were mixed and dissolved.

Example 4 According to Example 3, 10 parts of capric acid was changed to 10 parts of lauric acid.

Example 5 According to Example 3, 10 parts of capric acid was changed to 10 parts of oleic acid.

Example 6 According to Example 3, 10 parts of capric acid was changed to 10 parts of myristic acid.

Example 7 According to Example 3, 10 parts of capric acid was changed to 10 parts of caprylic acid.

Example 8 5 parts of tamsulosin free base and 95 parts of a fatty acid-containing polyaminoacrylate aqueous solution (Plastoid E35H; manufactured by Rohm & Pharma Co.) were taken and dissolved by heating at 140 ° C. After cooling to room temperature, it was spread on an aluminum laminated polyester film with a thickness of 100 μm, dried at 80 ° C. for 15 minutes, left overnight in a room temperature desiccator, and then covered with a silicon-coated polyethylene terephthalate film to a predetermined size. I cut it.

Example 9 5 parts of tamsulosin free base and 90 parts of a fatty acid-containing polyaminoacrylate aqueous solution (Plastoid E35H; manufactured by Rohm & Pharma) were taken and dissolved by heating at 140 ° C. After cooling to room temperature, isopropyl myristate (IP
M) 5 parts were added and mixed. Thereafter, it was manufactured according to Example 8.

Example 10 5 parts of tamsulosin free base and 85 parts of a fatty acid-containing polyaminoacrylate aqueous solution (Plastoid E35H; manufactured by Rohm & Pharma) were taken and dissolved by heating at 140 ° C. The solution was cooled to room temperature with stirring, 10 parts of isopropyl myristate (IPM) was added to uniformly precipitate crystals of tamsulosin free base, and then the film was spread on an aluminum laminated polyester film at a thickness of 350 μm and allowed to stand at room temperature. After leaving it in a desiccator overnight, it was covered with a silicon polyethylene terephthalate film and cut into a predetermined size.

Example 11 5 parts of tamsulosin free base and 80 parts of a fatty acid-containing aqueous polyaminoacrylate solution (Plastoid E35H; manufactured by Rohm & Pharma) were taken and dissolved by heating at 140 ° C. This liquid was cooled to room temperature with stirring, and 10 parts of isopropyl myristate (IPM) and methacrylic acid copolymer LD (Eudragit L30D-55;
(ROHM & PHARMA) 5 parts were added and mixed uniformly. This liquid was spread on an aluminum laminated polyester film with a thickness of 350 μm, dried at 80 ° C. for 30 minutes, covered with a silicon polyethylene terephthalate film, and cut into a predetermined size.

Example 12 5 parts of tamsulosin free base and 90 parts of a fatty acid-containing aqueous polyaminoacrylate solution (Plastoid E35H; manufactured by Rohm & Pharma) were taken and dissolved by heating at 140 ° C. After cooling to room temperature, isopropyl barmitate (IP
P) 5 parts were added and mixed, and the mixture was spread on an aluminum laminated polyester film at a thickness of 350 μm. 30 at 80 ℃
It was dried for a minute, covered with a silicon polyethylene terephthalate film, and cut into a predetermined size.

Example 13 In Example 9, 5 parts of IPM was changed to 5 parts of diethyl sebacate, and thereafter, production was carried out according to Example 9.

Example 14 15.9 parts of polyaminoacrylate (Eudragit E100; manufactured by Rohm & Pharma), 9.2 capric acid
Parts, 1.8 parts of adipic acid, and 79 parts of purified water were dissolved by stirring in a vacuum emulsifier at 80 ° C., and 1 part of glycerin and 0.1 part of 2% hydrogen peroxide solution were added to obtain an adhesive base. This adhesive base 8
Take 5 parts and add 5 parts tamsulosin free base 14
It melt | dissolved by heating at 0 degreeC. This solution was cooled to room temperature with stirring, 10 parts of isopropyl barmitate (IPP) was added, and 350 parts was added to the aluminum laminated polyester film.
It was spread at a thickness of μm and dried at 80 ° C. for 30 minutes. After drying, it was covered with a silicon polyethylene terephthalate film and cut into a predetermined size.

Example 15 The procedure of Example 14 was repeated except that the amount of the adhesive base was changed to 90 parts and the amount of IPP was changed to 5 parts.

Example 16 In Example 14, 10 parts of IPP was changed to 10 parts of IPM, and thereafter, production was carried out according to Example 14.

Example 17 In Example 16, 90 parts of the adhesive base and 5 parts of 10 parts of IPM were used.
Parts, and then manufactured according to Example 16.

Example 18 5 parts of tamsulosin free base and 5 parts of polyethylene glycol 400 were taken and melted by heating at 140 ° C., and an anionic poly (meth) acrylate aqueous solution (Plastoid L50; manufactured by Rohm & Pharma) 90 at room temperature. Parts were added and mixed uniformly. It was spread on an aluminum laminated polyester film with a thickness of 100 μm, dried at 80 ° C. for 15 minutes, left overnight in a room temperature desiccator, covered with a silicon-coated polyethylene terephthalate film, and cut into a predetermined size.

Example 19 2 parts of tamsulosin free base and 400 parts of polyethylene glycol were taken and heated and melted at 140 ° C.,
After cooling to room temperature, methyl acrylate / -2-ethylhexyl acrylate copolymer resin emulsion (Nikazol TS
620 (manufactured by Nippon Carbite Co., Ltd.), and mixed uniformly. This solution was spread on an aluminum laminated polyester film with a thickness of 100 μm, dried at 80 ° C. for 1 hour, covered with a silicon-coated polyethylene terephthalate film, and cut into a predetermined size.

Example 20 Polyethylene glycol 400, 18 of Example 19
The part was changed to 18 parts of propylene glycol, and the subsequent production was carried out according to Example 19.

Example 21 5 parts of tamsulosin free base and vinyl acetate-ethylene copolymer emulsion (Sumikaflex S-51
0, manufactured by Sumitomo Chemical Co., Ltd.) and uniformly mixed at room temperature to 100 μm on an aluminum laminated polyester film.
Was spread at a thickness of 80 ° C., dried at 80 ° C. for 1 hour, covered with a silicon-coated polyethylene terephthalate film, and cut into a predetermined size.

Example 22 5 parts of tamsulosin free base, 35 parts of hydroxypropyl cellulose (HPC-SL; Shin-Etsu Chemical Co., Ltd.) and 400 parts of polyethylene glycol were taken and mixed by heating at 140 ° C. This was poured into an aluminum foil cup (made by Marusho Co., Ltd.) and left overnight at room temperature to obtain a matrix. This was adhered to a ring-shaped backing material made of a plastic foam with an adhesive and covered with release paper to obtain a matrix preparation.

Example 23 Formulation Tamsulosin free base 1.5 parts Eudragit RS30D 80 polysorbate 802 triacetin 10 polyethylene glycol 400 6.5 6.5 ─────────────────────── ──────── 100 parts Tamsulosin free base 1.5 parts polysorbate 8
02 parts, 10 parts of triacetin and 6.5 parts of polyethylene glycol 400 are added and mixed in an oven at 100 ° C. After cooling to room temperature, Eudragit RS30D
(Product name, manufactured by Rohm & Pharma Co., general name; ethyl acrylate / methyl methacrylate / methacrylic acid trimethyl / ammonium ethyl copolymer aqueous dispersion)
80 parts were added and mixed. This was poured into an aluminum foil cup (manufactured by Marusho) and left overnight to obtain a matrix.
The molded body was adhered to a backing material made of a ring-shaped plastic foam with an adhesive. Finally, a release liner was covered to obtain a matrix preparation.

Example 24 Prescription tamsulosin free base 0.5 part ethanol 20 purified water 47.5 1,3-butylene glycol 30 l-menthol 2 ──────────────────── ──────────── 100 (wt%) A circular polyester non-woven fabric with a diameter of 2.5 cm (EL-6085 manufactured by Japan Vilene Co., Ltd.) is used as a drug-impermeable material, and has a diameter of 3.1 cm. It heat-sealed on a 50-micrometer-thick aluminum laminated polyester film, and was fixed on the film.

The molded body was made into a plastic foam with an adhesive having a diameter of 5.1 cm (manufactured by 3M, Form Tap).
It was adhered to the center of a backing material made of e9773).

Next, 300 mg of the above formulation was applied to the non-woven fabric part.
Dropped.

Finally, the side of the backing material on which the adhesive was applied was covered with release paper to obtain a pharmaceutical preparation.

Example 25 0.5 part of tamsulosin free base was mixed with 20 parts of ethanol.
Parts and purified water 46.5 parts, 1-menthol 2 parts, 1,3-
30 parts of butylene glycol was added and sufficiently stirred with a bath type ultrasonic generator. To this, 1 part of Duck Lloyd NF (trade name: manufactured by Kibun Food Chemifa Co., general name: propylene glycol alginate) was added, and a homomixer (Polytron PT10-35; trade name: Kinem) was added.
homogenized by ATICA (rotation speed 20,0)
(00 rpm, time: 3 minutes) In order to completely swell, the mixture was left to stand overnight and used as an external preparation.

As a drug impermeable material, a diameter of 3.1
An aluminum laminated polypropylene film having a thickness of 50 cm and a thickness of 50 μm was used, and 300 mg of the above gel formulation was dropped on the film.

Further, a porous polypropylene membrane (trade name: Celgard, manufactured by Hoechst) was overlaid and heat-sealed thereon, and the gel formulation was encapsulated to obtain a drug solution-containing molded product.

The molded body was formed by Form Tape, which is a plastic foam with an adhesive having a diameter of 5.1 cm and manufactured by 3M Co., Ltd.
9773. It was adhered to the center of the backing material.

Finally, a release liner was put on the adhesive-coated side of the backing material to obtain a pharmaceutical preparation.

Example 26 To 30 parts of diethyl sebacate, 2 parts of stearic acid and 0.5 part of tamsulosin free base were added and dissolved by heating, and then 4 parts of stearyl alcohol, 3 parts of glyceryl monostearate and polyethylene monostearate. 5 parts of glycol was added and heated to 70 ° C.

10 parts of 1,3-butylene glycol preheated to 70 ° C. and purified water 45.
5 parts of the aqueous phase component was gradually added with stirring to emulsify and gradually cooled to obtain a cream formulation containing tamsulosin free base.

Example 27 The tamsulosin free base-containing cream obtained in Example 26 was made into a patch by the method described in Example 25.

Example 28 5 parts tamsulosin free base and 5 parts capric acid were added.
Mix at 0 ° C, cool to room temperature, add 20 parts of chloroform and dissolve with stirring. Silicon oil 100 centistoke (Dow Corning, trade name; 360 Medical Fl)
uid) 4.2 parts and amine-resistant polydimethyl siloxane (Dow Corning, trade name; X7-4201)
65.8 parts were added and mixed uniformly. This was spread on a fluorocarbon-coated polyester film with a thickness of 300 μm, dried at 60 ° C. for 30 minutes, covered with an aluminum laminated polyester film, and cut into a predetermined size. The drug-containing adhesive layer of this percutaneous absorption preparation became white due to the precipitation of the drug after drying.

Example 29 6.25 parts tamsulosin free base, 6.
After mixing and dissolving 25 parts and 12.5 parts of PG at 80 ° C. and cooling to room temperature, 100 centistokes of silicone oil (Dow Corning, trade name; 360 Medical F
4.5 parts and amine-resistant polydimethylsiloxane (Dow Corning, trade name; X7-420)
1) 70.5 parts were added and mixed uniformly. This is 300μ
It was spread on a fluorocarbon-coated polyester film with a thickness of m, dried at 60 ° C. for 30 minutes, covered with an aluminum laminated polyester film, and cut into a predetermined size. The drug-containing adhesive layer of this transdermal preparation is slightly white after drying,
It was transparent.

Example 30 10 parts of tamsulosin free base, 10 parts of capric acid and 20 parts of PG were mixed and dissolved at 80 ° C., and after cooling to room temperature,
Silicon oil 100 centistoke (Dow Corning, trade name; 360 Medical Fluid)
3.6 parts and amine-resistant polydimethylsiloxane (Dow Corning, trade name; X7-4201) 56.
4 parts were added and mixed uniformly. This is spread on a fluorocarbon-coated polyester film with a thickness of 300 μm,
After drying at 60 ° C. for 30 minutes, it was covered with an aluminum laminated polyester film and cut into a predetermined size. The drug-containing adhesive layer of this transdermal preparation was slightly white and transparent after drying.

Example 31 In Example 29, 6.25 parts of capric acid was changed to 6.25 parts of lauric acid, and the preparation was carried out according to Example 29.

Example 32 5 parts of tamsulosin free base and 85 parts of a fatty acid-containing polyaminoacrylate aqueous solution (Plastoid E35H; manufactured by Rohm & Pharma) were taken and dissolved by heating at 140 ° C. This solution was cooled to room temperature with stirring, 10 parts of isopropyl myristate (IPM) was added, and spread on an aluminum laminated polyester film at 1 g / 50 cm ² ,
It was dried at 80 ° C. for 15 minutes, covered with a silicon polyethylene terephthalate film, and cut into a predetermined size.

The physicochemical properties of tamsulosin (free base) contained as a drug in the percutaneously absorbable preparation of the present invention are described below.

Melting point: 130.8 ° C. Measuring apparatus: Miyamoto RIKEN PA-20S melting point measuring apparatus Measuring method: Japanese Pharmacopoeia 12th revision, melting point measuring method (No. 1)
According to the law).

DSC (see FIG. 1 below): Endothermic peak is a single peak, rising temperature 128 ° C. Measuring device: Rigaku PTC-10A type Measuring method: Temperature rising from 45 ° C. to 200 ° C. at 10 ° C./min.

[0101]

INDUSTRIAL APPLICABILITY The percutaneous absorption preparation or the α1 receptor blocker of the present invention is preferably a transdermal preparation for α1 receptor blockade or an α1 blocker for transdermal absorption, and tamsulosin having an α1 receptor blocker action. The free base has excellent transdermal permeability and enables the formulation of a practical TTS.
As a formulation of TS, an accurate α
It is useful for achieving in vivo absorption of tamsulosin, which is necessary to exert the 1-receptor blocking effect. With the formulation technology of the present invention, a good transdermal absorption effect of tamsulosin free base and a combination of several types of strong transdermal absorption enhancers, which were indispensable conditions in the prior art, and an optimum dosage form, and The α1 receptor blocking effect can be achieved.
The composition of the present invention is also useful as a percutaneous absorption preparation or an α1 receptor blocker having excellent transdermal absorbability such as conventional patches, ointments such as gel ointments, emulsions and solutions.

The excellent effect of promoting percutaneous absorption of the preparation of the present invention was confirmed by the following method.

[Preparation Method] According to the method described in Examples 1 and 2, an external preparation was prepared. A control solution (Control Examples 1 and 2) was prepared in the same manner as in Examples 1 and 2 except that the same amount of tamsulosin hydrochloride was used instead of tamsulosin free base. Also, a transdermal preparation was prepared according to the method described in Example 32. Control Example 3 was prepared using the same amount of tamsulosin hydrochloride instead of tamsulosin free base.

[Test Method] As a percutaneous absorption test, in vitro using miniature pig (yucatan microswine) skin.
It was evaluated by a skin permeability test.

The mini-pig skin was mounted on a Franz type diffusion cell (cell effective area: 0.7 cm ² ), the sample was added to the donor side, and an isotonic 10 mM potassium dihydrogen phosphate solution was added to the receptor side. Experimented at 37 ° C. After 4, 8 and 24 hours, all receptor samples were collected and the concentration of tamsulosin permeated through the skin was quantified by liquid chromatography. For the evaluation of the tape preparation, the same test was conducted after adhering the tape preparation, which was cut into 2 cm square in advance, to the skin of the mini pig.

[Result]

[Table 1]

[0107]

[Table 2]

Control Example 3 5 parts of tamsulosin free base in Example 32 was changed to 5 parts of tamsulosin hydrochloride, and the preparation was carried out according to Example 32.

[Table 3] Mini-pig skin permeability (n = 3)

As is clear from the results of Tables 1, 2 and 3, the percutaneous absorption preparation of the present invention exhibits a superior transdermal absorption effect as compared with the control example, and the accumulated permeation amount after 24 hours. And the permeation rate was about 4 times higher than that of the control.

Regarding the effect of the percutaneously absorbable preparation of the present invention, a skin permeability test was conducted in the same manner as in the above test methods in the formulations of Examples 3 to 6. As a result, the cumulative amount of permeation (μg / cm ² ) and the permeation rate (μg / cm ² ) of each example up to 24 hours.
/ Hr) is shown in Table 4. It has been found that the transdermal absorbability of tamsulosin free base is significantly increased by using higher fatty acids. It has been revealed that this absorption promoting effect greatly differs depending on the type of higher fatty acid used, and that particularly capric acid and lauric acid exhibit excellent effects.

[Table 4]

Regarding the effect of the percutaneous absorption preparation of the present invention, a skin permeability test was conducted in the same manner as in the above test methods in the formulations of Examples 9 to 13. As a result, the cumulative permeation amount (μg / cm ² ) and permeation rate (μg / c) of each example up to 24 hours.
m ² / hr) is shown in Table 5. Fatty acid-containing polyaminoacrylate aqueous solution (Eudragit E35H; ROHM &
It was revealed that the transdermal absorbability of tamsulosin free base using Pharma Co., Ltd. as an adhesive was increased by the addition of the higher fatty acid ester, and from the results of Examples 9 and 10, the higher concentration of the higher fatty acid ester was added. It was revealed that the transdermal absorbability was increased.

[Table 5]

Regarding the effect of the percutaneous absorption preparation of the present invention, a skin permeability test was conducted in the same manner as in the above test method in the formulations of Examples 14 to 17. As a result, the cumulative permeation amount (μg / cm ² ) and permeation rate (μg / c) of each example up to 24 hours.
m ² / hr) is shown in Table 6. Higher transdermal absorption of tamsulosin free base was obtained also by adding higher fatty acid ester to the polyaminoacrylate adhesive containing capric acid. It was also clarified that the percutaneous absorbability was increased by increasing the concentration of higher fatty acid ester added.

[Table 6]

Regarding the effect of the percutaneously absorbable preparation of the present invention, a skin permeability test was conducted in the same manner as in the above test method in the formulations of Examples 28 to 30. As a result, the cumulative permeation amount (μg / cm ² ) and permeation rate (μg / c) of each example up to 24 hours.
m ² / hr) is shown in Table 7. The percutaneous absorbability of tamsulosin free base was confirmed to be absorption promoting effect by adding higher fatty acid in the silicone adhesive. It was further observed that the transdermal absorbability was further increased by adding glycols to increase the solubility of the drug.

[Table 7]

[Test Method] Rat in Vivo Absorption Experiment On the day before the test, the abdominal skin of a rat (Fisher, male, 7 weeks old) was hair-removed using an electric clipper and a hair removal cream (Eva Claim; manufactured by Tanabe Seiyaku Co., Ltd.). did. On the test day,
The tape preparation was attached to the shaved abdominal skin, and a plastic foam (3M, Form tape 9) with an adhesive was applied.
773) and then covered with an adhesive bandage (Elastopore manufactured by Nichiban Co., Ltd.). Blood was collected 3 hours, 9 hours, 18 hours, 24 hours, and 48 hours after administration, and tamsulosin concentration in plasma was measured by HPLC.

[0115]

[Table 8] As is clear from the results in Table 8, the percutaneous absorption preparation of the present invention was confirmed to have excellent percutaneous absorption even in vivo.

[Primary Skin Irritation Test] The day before application, rabbits (17-week-old, Japanese white rabbit, male, Kitayama Labes Kbl:
The back of (JW) was shaved using an electric clipper. On the day of the test, the test substance was attached to the shaved back skin, and a plastic foam (3M, Form tape9) with an adhesive was attached.
It was fixed with 773) and further covered with a stretch net. The application time is 24 hours, and 1 hour after removing the test substance, Draiz
The skin reaction was observed and evaluated according to the criteria of e.

[0117]

[Table 9] Results of primary skin irritation test As is clear from the results in Table 9, all the transdermal preparations of the present invention had slight skin irritation. In particular, a polyaminoacrylate adhesive containing capric acid (Example 14
.About.17) and the silicone adhesive (Example 29) were extremely slight skin irritation.

[0118]

[Brief description of drawings]

FIG. 1 is a diagram showing a measurement result of DSC of tamsulosin free base (in the figure, each line of and is DS.
C, showing temperature. ).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 9/70 352 A61K 9/70 352 354 354 363 363 47/10 47/10 G 47/12 47 / 12 EG 47/14 47/14 EG (72) Inventor Tatsuo Yasuda 3-3-43 Ogawa Shinmachi, Yaizu City, Shizuoka Prefecture (72) Inventor Muneo Fukui 5-13-14 Minamisurugadai, Fujieda City, Shizuoka Prefecture

Claims (16)

[Claims] 1. The following formula: A percutaneous absorption preparation comprising a tamsulosin free base represented by: 2. The following formula: A transdermal preparation for blocking α1 receptor, which comprises a tamsulosin free base represented by: 3. The transdermal tissue according to claim 1, which contains an acrylic adhesive or a silicone adhesive, and further contains a transdermal absorption enhancer and / or a dissolving agent. Absorption formulation. 4. The percutaneous absorption preparation according to claim 3, wherein the percutaneous absorption promoter is a higher fatty acid ester and / or a higher fatty acid. 5. The percutaneous absorption preparation according to claim 3, wherein the solubilizer is one or more selected from the group consisting of glycols, fatty acids, triethyl citrate and triacetin. 6. The percutaneous absorption preparation according to claim 3, wherein the higher fatty acid ester is one or more selected from the group consisting of isopropyl myristate, isopropyl palmitate and diethyl sebacate. . 7. The percutaneous absorption preparation according to claim 3, wherein the higher fatty acid is capric acid and / or lauric acid. 8. The percutaneous absorption preparation according to claim 3, wherein the glycol is one kind or two or more kinds selected from the group consisting of propylene glycol, polyethylene glycol and 1,3-butylene glycol. . 9. The acrylic pressure-sensitive adhesive is a methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, lauric acid, adipic acid, glycerin,
A fatty acid-added polyaminoacrylate aqueous solution containing hydrogen peroxide and water (generic name; trade name: plastoid E,
The product for transdermal absorption according to claim 3, which is manufactured by Rohm & Pharma. 10. The acrylic pressure-sensitive adhesive is composed of a methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, capric acid, adipic acid, glycerin, hydrogen peroxide solution and water. The percutaneous absorption preparation according to 3. 11. The percutaneous absorption preparation according to claim 9 or 10, which contains isopropyl palmitate as a percutaneous absorption enhancer. 12. The percutaneous absorption preparation according to claim 9, which contains isopropyl myristate as a percutaneous absorption enhancer. 13. The percutaneous absorption according to claim 3, further comprising a silicone adhesive, further comprising capric acid as a percutaneous absorption enhancer and / or a dissolving agent, and propylene glycol as a dissolving agent. Formulation. 14. The percutaneous absorption according to claim 3, further comprising a silicone adhesive, further comprising lauric acid as a percutaneous absorption enhancer and / or a dissolving agent, and propylene glycol as a dissolving agent. Formulation. 15. The following formula: An α1 receptor blocker comprising a tamsulosin free base represented by: 16. The following formula: An α1 receptor blocker for transdermal absorption, which comprises a tamsulosin free base represented by: