JPS62228015A - Medicinal pharmaceutical for external use - Google Patents

Abstract

PURPOSE:The titled pharmaceutical, obtained by forming an adhesive layer consisting essentially of 4-[2-hydroxy-3-(isopropylamino)propoxy]-indole and a decomposition inhibitor thereof on one side of a carrier, capable of stably acting for a long period without side effect and having great hypotensitve effect. CONSTITUTION:A medicinal pharmaceutical for external use obtained by forming an adhesive layer consisting essentially of 4-[2-hydroxy-3-(isopropylamino) propoxy]indole having beta-blocking action and a decomposition inhibitor on one side of a carrier. A carrier capable of following a curve of the skin for application, e.g. polyolefin, polyurethane, etc., is preferred for the carrier. Examples of the decomposition inhibitor include succinic acid, polyphosphoric acid and/or sodium salt thereof, etc., and the amount of thereof used is within the range of 0.1-5wt%, preferably 0.2-3.0wt%.

Description

DETAILED DESCRIPTION OF THE INVENTION (1) Industrial Application Field The present invention is applied to the outer skin to obtain 4-[2-hydroxy-3-(
isopropylamino) propoxy 1-indole (hereinafter referred to as
This invention relates to the improvement of external pharmaceutical formulations that allow pindolol (referred to as pindolol) to be absorbed into the body, and more specifically, to an external pharmaceutical formulation that suppresses the decomposition of pindolol in the formulation and improves the stability of the formulation.

(b) Prior Art Pindolol has an excellent β-blocking effect and is evaluated not only in Europe and America but also in Japan as a useful antihypertensive agent as well as in the treatment of angina pectoris and arrhythmia.

Conventionally, pindolol has been used as an oral or injectable drug, but side effects such as headache, muscle pain, and nausea are likely to occur, and the oral drug requires administration three times a day, resulting in few subjective symptoms. , in many patients with essential hypertension who require long-term use of antihypertensive drugs.
Taking the medication once in a while is very cumbersome, so there is a risk of forgetting to take it, leading to insufficient control of blood pressure.

Furthermore, antihypertensive diuretics, which are often used in combination with β-blockers such as pindolol, are generally said to keep blood pressure under control throughout the day when administered once a day, so β-blockers may only need to be administered once a day. There was a strong desire to develop a formulation with a long action time.

Therefore, the present inventors have made extensive studies to solve the above problems, and have developed a pharmaceutical preparation containing pindolol in an adhesive with good skin adhesion.

(c) Problems to be Solved by the Invention This pharmaceutical preparation can be applied to the skin and its active ingredient, pindolol, can be absorbed into the body through the skin and maintain a stable plasma concentration over a long period of time. Pindolol was extremely unstable, and pindolol decomposed in the adhesive after long-term storage, making it unable to withstand long-term storage.

(d) Means for Solving the Problems Therefore, as a result of further research, the present inventors discovered that specific substances such as succinic acid are extremely effective in inhibiting the decomposition of pindolol. It has been completed.

That is, the present invention is characterized in that an adhesive layer containing 4-[2-hydroxy-3-(isopropylamino)propoxy]indole and a decomposition inhibitor thereof as essential components is formed on one side of the carrier. It is. □The present invention will be explained in detail below.

The carrier used in the present invention is not particularly limited as long as it supports an adhesive layer containing pindolol, and examples include polyolefin, polyurethane, polyvinyl alcohol, polyvinylidene chloride, polyamide, and ethylene-vinyl acetate copolymer. Examples include plastic films or sheets such as rubber and/or synthetic U (oil-based foamed films or sheets, metal foils, papers, non-woven fabrics, woven fabrics, or laminated forms of these), but preferably those in the form of curvature of the applied skin surface. It is desirable to have sufficient flexibility to conform.

Further, the adhesive layer used in the present invention is a layer formed of an adhesive exhibiting pressure-sensitive adhesive properties.

The above-mentioned pressure-sensitive adhesive is not particularly limited, and specifically, the following can be exemplified.

As an acrylic adhesive, for example, (meth)ac+7
(meth)acrylic acid 7'tyl ester, (meth)acrylic acid pentyl ester, (meth)acrylic acid hexyl ester, (meth)acrylic acid heptyl ester, (meth)acrylic acid octyl ester, (meth)acrylic acid nonyl ester,
Homopolymers of (meth)acrylic acid alkyl esters, such as (meth)acrylic acid decyl ester, (meth)acrylic acid undecyl ester, (meth)acrylic acid dodecyl ester, (meth)acrylic acid tridecyl ester, or the esters. and a copolymerizable monomer.

Examples of monomers that can be copolymerized include carboxyl group-containing monomers such as (meth)acrylic acid, itaconic acid, crotonic acid, maleic acid, maleic anhydride, and hexamaric acid, styrene sulfonic acid, and allyl sulfonic acid. , sulfoxyl group-containing monomers such as sulfopropyl acrylate, (meth)acryloyloxynaphthalenesulfonic acid, acryloyloxybenzenesulfonic acid, hydroxyl group-containing monomers such as (meth)acrylic acid hydroxyethyl ester, (meth)acrylic acid hydroxypropyl ester Monomer, (meth)acrylamide, dimethyl(meth)acrylamide, N-butylacrylamide, tetramethylbutylacrylamide, N-methylol(meth)acrylamide, an acrylic monomer containing an amide group, (meth)
Acrylic acid amine 7 ethyl ester, (meth)acrylic acid dimethylaminoethyl ester, (meth)acrylic acid diethylaminoethyl ester, (meth)acrylic acid te
Alkylaminoalkyl group-containing acrylic monomers such as rt-butyl ester, (meth)acrylic acid methoxyethyl ester, (meth)acrylic acid ethoxyethyl ester, (meth)acrylic acid butoxyethyl ester, (
meth)acrylic acid tetrahydrofurfuryl ester, (
Methoxyethylene glycol ester (meth)acrylate, methoxydiethylene glycol (meth)acrylate ester, methoxypolyethylene glycol (meth)acrylate, methoxypolypropylene glycol (meth)acrylate, and alkoxy groups (or ether bonds in side chains). Containing monomers, vinyl monomers such as N-(meth)acryloyl amino acids, functional monomers such as acrylic monomers such as urethane, urea, and incyanate esters of acrylic acid, and (meth)acrylonitrile. , vinyl acetate, vinyl propionate, vinylpyrrolidone, vinylpyridine, vinylpyrazine, vinylpiperazine, vinylpiperidone, vinylpyrimidine, vinylvirol, vinylimidazole, vinylcaprolactam,
Vinyloxazole, vinylthiazole, vinylmorpholine, styrene, α-methylstyrene, bis(N,N-
Examples include vinyl monomers such as trimethylaminoethyl) maleate.

In the present invention, the (meth)acrylic acid alkyl ester and the copolymerizable monomer include various isomers in which the alkyl moiety is linear or branched, as well as various isomers and derivatives in which the position of the substituent group is different. It is something.

Examples of other adhesives include silicone rubber, polyisoprene rubber, polyisobutylene rubber, polybutadiene,
Rubber materials such as styrene-butadiene (or isoprene)-styrene block copolymer rubber, acrylic rubber, natural rubber, polyvinyl alkyl ether, polyvinyl acetate, partially saponified polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone, etc. External vinyl polymer substances, cellulose derivatives such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose,
Polysaccharides such as pullulan, dextrin, and agar, polyurethane elastomers, polyester elastomers, and water-soluble acrylics such as polyacrylic acid (or salts thereof), polymethacrylic acid (or salts thereof), and carboxyvinyl polymers. Water-containing polymers containing a polymer, a polyhydric alcohol such as glycerin, a crosslinking agent such as triglycidyl isocyanate, and water can also be used.

In addition, when using the above adhesive, if there is a risk of adhesive remaining on the skin surface after application due to insufficient cohesive force and contaminating the skin surface, do not impair skin adhesion. It is preferable to subject the pressure-sensitive adhesive to a moderate degree of chemical crosslinking or physical crosslinking.

In the present invention, the above pressure-sensitive adhesive (A) includes pindolol (
B) is added, but the amount of (B) added is the same as that of (A) and (B).
), preferably 2 to 2% by weight based on the total amount of
It is desirable to set the content to 0% by weight from the viewpoint of both the effectiveness and economical efficiency of pindolol.

The most significant feature of the present invention is that pindolol, its active ingredient, and a decomposition inhibitor thereof coexist in the external pharmaceutical preparation.

Examples of the decomposition inhibitor include succinic acid, polyphosphoric acid and/or its sodium and potassium salts, and the sodium salt of ethylenediaminetetraacetic acid.

This decomposition inhibitor suppresses the decomposition reaction of pindolol,
It is added in order to stabilize pindolol over a long period of time, and the amount added is 0.1 to 5% by weight, preferably 0.2 to 3.0% by weight, based on the total weight of the adhesive and pindolol.
It is used in the range of 0% by weight, and if the amount added is less than 0.1% by weight, it is difficult to obtain the desired effect, and if the amount added is more than 5% by weight, there is a limit to the effect, and it is also undesirable from the viewpoint of skin irritation. The cohesive force of the adhesive may also deteriorate, and adhesive residue may be left on the skin surface to which it is applied.

In the present invention, in order to improve the transdermal absorption of pindolol in the adhesive layer, if desired, an aid for improving the solubility of pindolol and promoting the transdermal absorption of pindolol such as a keratin softener is added to the adhesive layer. It is possible to do so.

Examples of this type of auxiliary agent include lower alcohols such as ethanol, glycols such as ethylene glycol, triethylene glycol, polyethylene glycol, and propylene glycol, polyhydric alcohols such as glycerin and sorbitol, urea, dimethyl sulfoxide, dimethyl acetamide, dimethyl Examples include formamide, diethyl sebacate, propylene carbonate, imigzolidinone derivatives, N-methyl-2-pyrrolidone, and various surfactants, and at least one of these is added.

The mixing ratio of the pindolol-containing pressure-sensitive adhesive (C) and the pindolol absorption promoting aid (D) is such that (D) is the same as the above (C).
) and (D) is preferably in the range of 0.5 to 20% by weight, if it is less than 0.5% by weight, the effect as an auxiliary agent is poor, while if it exceeds 20% by weight, This is not preferable because it causes problems in skin adhesion, 2-layer adhesiveness, etc.

In the external pharmaceutical preparation of the present invention, the exposed surface of the adhesive layer formed on the surface of the carrier is protected by covering it with a flexible release film such as polyethylene terephthalate that has been subjected to release treatment. preferable.

The external pharmaceutical preparations of the present invention are preferably stored and distributed individually or in bulk in bags made of packaging material with excellent moisture impermeability, such as a laminate film of aluminum foil and plastic film.

(e) Effect In the present invention, the reason why a specific substance such as succinic acid suppresses the decomposition of pindolol is not clear, but it is possible that pindolol and a decomposition inhibitor such as succinic acid form some kind of bond or form a complex through interaction. This is thought to be due to the formation of pin rolls, which stabilized the pin rolls.

(f) Examples The present invention will be explained in more detail by examples below.
The present invention is not limited to this.

In addition, parts or % in Examples and Comparative Examples mean parts by weight or % by weight.

Example 1 9'5 g of acrylic acid 2-ethylhexyl ester and 5 parts of acrylic acid were placed in a flask under an inert gas atmosphere, and 0.3 g of azobisisobutyronitrile was added as a polymerization initiator.
part was added to initiate polymerization.

The internal temperature was controlled at 58 to 62°C by adjusting the stirring speed and external temperature and dropping ethyl acetate, and polymerization was carried out for 8 hours to obtain an acrylic adhesive (Tg = -43°C) solution.

Pindolol and sodium polyphosphate were added and mixed to the obtained acrylic adhesive solution, and this was coated and dried on the release liner so that the coating thickness after drying was 40 μm to form an adhesive layer. The external pharmaceutical formulation of the present invention was obtained by transferring the mixture onto a Bo-17 ethylene film.

In this case, the content of pindolol or sodium polyphosphate in the adhesive layer is 5% or 1%, respectively.

Example 2 55 parts of 2-ethylhexyl acrylate, 15 parts of 2-ethoxyethyl acrylate, and 30 parts of vinyl acetate were charged into a flask under an inert gas atmosphere, and 0.2 parts of benzoyl peroxide was added as a polymerization initiator. was added to initiate polymerization. Next, in the same manner as in Example 1, the inner pond temperature was controlled at 58 to 62°C, and a polymerization reaction was carried out for about 12 hours to obtain an acrylic pressure-sensitive adhesive (T, = -30°C) solution.

Pindolol and succinic acid were added to and mixed with the obtained acrylic adhesive solution, and the same procedure as in Example 1 was performed to obtain an external pharmaceutical preparation of the present invention.

In this case, the content of pindolol or succinic acid in the adhesive layer is 7.5% or 1%, respectively.

Example 3 Pindolol and tetrasodium ethylenediaminetetraacetate were added to and mixed with the acrylic adhesive solution obtained in Example 2, and the same procedure as in Example 1 was performed to obtain an external pharmaceutical preparation of the present invention.

In this case, the content of pindolol or tetrasodium ethylenediaminetetraacetate in the adhesive layer is 10% or 2%, respectively.
．． It is 0%.

Example 4 2-ethylhexyl acrylate 9ON6 and 10 parts of N-vinyl-2-pyrrolidone were charged in 7 rasfs under an inert gas atmosphere, and 0.3 part of azobisisobutyronitrile was added as a polymerization initiator. Polymerization was started. Next, the internal temperature was lowered to 57 to 60°C by the same operation as in Example 1.
Polymerization was carried out for 8 hours under the control of acrylic adhesive (Tg=
-41°C) solution was obtained.

Pindolol and disodium ethylenediaminetetraacetate were added to and mixed with the obtained acrylic pressure-sensitive adhesive solution, and the same procedure as in Example 1 was carried out to obtain an external pharmaceutical preparation of the present invention.

In this case, the content of pindolol or disodium ethylenediaminetetraacetate in the adhesive layer is 5% or 1%, respectively.
It is.

Example 5 Pindolol and succinic acid were added to and mixed with the acrylic adhesive solution obtained in Example 1, and the same procedure as in Example 1 was performed to obtain an external pharmaceutical preparation of the present invention.

In this case, the content of pindolol or succinic acid in the adhesive layer is 5% or 1%, respectively.

Example 6 Pindolol and potassium polyphosphate were added to and mixed with the acrylic adhesive solution obtained in Example 2, and the same procedure as in Example 1 was performed to obtain an external pharmaceutical preparation of the present invention.

In this case, the contents of pindolol and potassium polyphosphate in the adhesive layer are 5% and 1%, respectively.

Comparative Examples 1 to 6 Comparative Examples 1 to 6 correspond to Examples 1 to 6, and from each example, sodium polyphosphate, succinic acid, ethylenenoaminetetraacetic acid, lithium, and ethylenenoamine were used. Except for disodium tetraacetate, succinic acid, and potassium polyphosphate, the other conditions were the same as in each example.

Table 1 shows the stability of each Example and each Comparative Example, and Table 2 shows the change in blood concentration at each time when these were applied to the skin surface. In addition, each test method is as follows.

<Survival rate of pindolol> Each example and each comparative example was stored at a temperature of 50°C for 3 months, then cut into regular shapes (n = 16), extracted with 7-tar, and subjected to high-performance liquid chromatography. Quantitated. In addition, the residual rate of pindolol was calculated using the following formula.

<Blood concentration> Three test pieces (1, Oc + n square) of each example and each comparative example were
After pasting it on the inside of the upper arm of three men aged 0 to 45 years, blood was collected at predetermined intervals of 5 mN and plasma was separated.
-15- A mixed solution of n-amyl alcohol and n-hebutane (isoamyl alcohol content: 6%) was extracted with pindolol at 1.0 mf, and then centrifuged to separate the organic solvent layer.

Furthermore, 0.0% is added to this organic solvent layer. Add 2 m of INN hydrochloric acid, separate the extracted condensate layer, and add 0.1 m of O-7 taraldehyde to this.
After reacting for 20 minutes at 60°C, cool to 0.
．． A 5 mf ascorbic acid solution was added and quantified using fluorescence analysis.

(Leaving space below) It is clear from Table 1, Table 2, and Table 1 that the example product has extremely superior pin roll stability compared to the comparative example product.
Furthermore, from Table 2, it is recognized that there is no inferiority in terms of absorption of pindolol.

(8) Effects of the Invention As stated above, the external pharmaceutical preparation of the present invention contains pindolol and its decomposition inhibitor as essential components, and the decomposition inhibitor suppresses the decomposition of pindolol for a long period of time.
This has the effect of stabilizing the formulation over a long period of time.

Claims (2)

[Claims] (1) 4-[2-hydroxy-3-(
1. A pharmaceutical preparation for external use, comprising an adhesive layer containing as essential components an isopropylaminopropoxy]indole and a decomposition inhibitor thereof. (2) The external pharmaceutical preparation according to claim 1, wherein the decomposition inhibitor is at least one of succinic acid, polyphosphoric acid and/or its sodium and potassium salts, and the sodium salt of ethylenediaminetetraacetic acid.