JPH11335277A - Percutaneously absorbable type plaster - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation easy to control the dose of the medicinal ingredient with high percutaneous infiltrativity thereof, capable of mitigating side effects and maintaining stable efficacy, by incorporating a specific medicinal ingredient in a specific tacky base so as to bring the percutaneous infiltration rate of the medicinal ingredient per unit area in the stationary state within a specific range. SOLUTION: This preparation is obtained by incorporating 4-amino-3,5 dichloro-α-[(1,1-dimethyl)aminomethyl]benzenemethanol as medicinal ingredient in a tacky base consisting of an elastic polymer of the formula (A-B)n -A (A is a substantially monovinyl-substituted aromatic compound polymer block; B is a substantially conjugated diolefin polymer block; (n) is 3-7) so as to be 0.15-4.0 μg/cm<2> /h in the percutaneous infiltration rate of the medicinal ingredient per unit area in the stationary state Flux<ss> [Flux<ss> is a (medicinal-specific systemic clearance × effective blood concentration)/effective administration area] in terms of human skin and 0.5-10 cm<2> in the effective administration area of the tacky base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 4-amino-3,5-
By containing transdermally containing dichloro-α-[((1,1-dimethylethyl) amino) methyl] benzenemethanol (hereinafter referred to as “the present drug”), it is possible to achieve a stable drug blood concentration over time. It relates to a transdermal patch.

[0002]

2. Description of the Related Art 4-Amino-3,5-dichloro-α-
[((1,1-dimethylethyl) amino) methyl] benzene methanol, at beta ₂ receptor selectivity of beta-agonists, bronchial asthma exhibit selective bronchodilation, chronic bronchitis, pulmonary airways, etc. It has been used as a therapeutic agent for remission of various symptoms such as dyspnea due to airway obstructive disorder. 4
Tablets and granules are known as a preparation of -amino-3,5-dichloro-α-[((1,1-dimethylethyl) amino) methyl] benzenemethanol. This drug has good properties of absorption and sustained efficacy when administered orally, and its biological half-life is as long as about 35 hours. However, side effects of the circulatory system such as an increase in heart rate, side effects of the nervous system such as tremor, headache, excitement, and dizziness, and digestive side effects such as nausea and anorexia have become problems. The cause is thought to be a temporary increase in blood levels following oral administration.

[0003] On the other hand, as a means for solving these drawbacks, attempts have been made by transdermal administration. For example, JP-A-63
JP-10716 proposes an external preparation for percutaneously absorbing 4-amino-3,5-dichloro-α-[((1,1-dimethylethyl) amino) methyl] benzenemethanol. This formulation is 4-amino-3,5-dichloro-α-[((1,1-dimethylethyl) amino)
Methyl] benzenemethanol is intended to control a temporary increase in blood concentration during oral administration by using a novel dosage form mainly composed of an ointment or cream. However, this topical preparation is expected to maintain its efficacy compared to conventional oral preparations, but it is difficult to strictly control the dosage of ointments and creams after application, as the medicinal ingredients are scraped off by clothing etc. . In addition, those disclosed as solubilizers are generally described as alcohols, glycols, fatty acid esters, mineral oils, propylene carbonate, N-methylpyrrolidone, etc. Only some of alcohols, glycols and fatty acid esters have been studied. In addition, fatty acid esters act as a solubilizing agent when the drug is a free base, but do not act as a solubilizing agent when a hydrochloride is used. Further, N-methylpyrrolidone acts as a solubilizing agent for the drug. Although recognized, the activity of the drug in the base is reduced, which inhibits percutaneous absorption and hinders formulation. Furthermore,
Patches that are simple to administer and that allow relatively easy control of drug dose have not been studied. Further, a physiologically active substance, an organic acid (aliphatic carboxylic acid, aromatic carobonic acid, alkylsulfonic acid, alkylsulfonic acid derivative, cholic acid derivative or a water-soluble inorganic salt thereof), a hydrophobic polymer, a tackifier resin, Examples of a tape preparation having a pressure-sensitive adhesive layer containing a plasticizer and an absorption promoter (L-menthol, lauryl alcohol or pyrothiodecane) (International Publication WO 96/16642) have been reported. Although the aim is to improve the permeability of the drug through the drug, the problem of irritation to the skin by organic acids, and the amount of drug released has not been sufficiently effective in treatment, further study of the drug. Not.

[0004]

SUMMARY OF THE INVENTION Accordingly, the present invention has been made to solve the above-mentioned drawbacks, and an object of the present invention is to control the dosage of the drug by containing the pharmaceutically active ingredient. It is a preparation with high skin permeability, in which the administration method can be easily performed and a sufficient amount of the drug is supplied even in a small area. Another object of the present invention is to provide a percutaneously absorbable patch of a novel formulation capable of reducing the occurrence of side effects and maintaining a stable effect by maintaining a stable blood concentration.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies on the formulation of the formulation in order to develop the above-mentioned formulation, and as a result, the (AB) n-A type elastic polymer was mainly used. A medicinal ingredient, 4-amino-3,5-dichloro-α-[((1,1-dimethylethyl) amino) methyl] benzenemethanol, is blended in the pressure-sensitive adhesive layer. the ^ss value in human skin equivalent 0.15~ 4.0μg / cm ² / h
r range, and furthermore, the effective administration area range is 0.5-10cm
^By using the matrix type patch specified in ² , the transdermal patch of the above-mentioned purpose could be completed.

[0006]

(Equation 2)

[0007] The flux of a drug is a value used in pharmacokinetics and is used as a steady state unit area skin permeation rate for the development of a drug for external use.

The (AB) nA type elastic polymer used as an adhesive base of the transdermal patch of the present invention comprises:
Specifically, styrene-butadiene-styrene block copolymer (Clayton D-1101), styrene-isoprene-styrene block copolymer (Clayton D-1107, Clayton D-1111) available from Shell Chemicals, which are commercially available, and the like. And a styrene-isoprene-styrene block copolymer is particularly preferable. By using such an (AB) nA type elastic body as a formulation base, the release of the drug and the bioavailability can be significantly improved.

Next, the transdermal patch of the present invention will be specifically described. The drug of the present invention, which is a medicinal ingredient used in the present invention, is usually provided as a hydrochloride, but may be used as a hydrochloride in the transdermal patch of the present invention or as a free base. However, they generally have poor solubility and require a dissolution aid.

In the transdermal patch of the present invention, in order to control the blood concentration of the active ingredient in the effective range, it is necessary to control the absorption rate in the body by the clearance inherent in the body. The ideal drug absorption rate when the drug is transdermally administered is about 1.5 to 2.0 μg / hr, and the effective administration area is 0.5
It must be controlled in the range of 0.15~ 4.0μg / cm ² / hr in human skin in terms of the absorption rate per unit area at the time of ~10cm ^2. If the absorption rate is faster than this, side effects and irritation to the skin become problems. On the other hand, if it is lower than this, a therapeutic effect cannot be expected. The percutaneous absorption rate of rat skin used in experiments and the like is higher than that of human skin to be actually applied, and is said to be 2 to 10 times that of human skin.

The absorption aid for controlling the steady-state skin permeation rate of the drug in the present invention includes higher fatty acid esters having 7 or more carbon atoms (7 or more carbon atoms) and higher aliphatic alcohols (7 or more carbon atoms). Is used. As the higher fatty acid ester having 7 or more carbon atoms and the higher aliphatic alcohol to be used, a higher fatty acid ester or a higher aliphatic alcohol obtained from a fatty acid having 6 to 18 carbon atoms and an alcohol having 1 to 20 carbon atoms is used. Examples of the fatty acids having 6 to 18 carbon atoms that can form such higher fatty acid esters or higher fatty alcohols include adipic acid, myristic acid, palmitic acid, oleic acid, vaccenic acid, linoleic acid, and linolenic acid. Examples of the alcohol having 1 to 20 carbon atoms include methanol, ethanol, propanol,
Examples include isopropanol, butanol, hexanol, pentanol, heptanol, octanol, decanol, and cetanol. Higher fatty acid esters include isopropyl myristate, diisopropyl adipate, diethyl sebacate and the like, and higher aliphatic alcohols include myristyl alcohol and oleyl alcohol. One or a combination of two or more of the above fatty acid esters and / or aliphatic alcohols may be used. N-methyl-2-pyrrolidone is used as a dissolution aid for the present drug, but the aid tends to promote percutaneous absorption in the negative direction, and in the case where the skin permeation rate is too high, It also has a function as an absorption control agent.

The nonionic surfactants used in the present invention include glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene alkyl ethers, and polyoxyethylene hydrogenated castor oil. One or a combination of two or more of the above nonionic surfactants may be used.

A tackifying resin may be added to the adhesive base layer of the transdermal patch of the present invention. For example, rosin derivatives (eg, rosin, glycerin ester of rosin, hydrogenated rosin, hydrogenated rosin) Glycerin ester), alicyclic saturated hydrocarbon resin, polyterpene resin and the like.

[0014] A plasticizer may be added to the adhesive base layer of the transdermal patch of the present invention. For example, petroleum hydrocarbons (liquid paraffin), crotamiton, N-methyl-2-
Examples include pyrrolidone, liquid rubber (for example, polybutene and liquid isoprene rubber), and liquid polybutene rubber.

As a support for a tape preparation, a patch and a cataplasm, a support usually used for a patch is used. Materials for such a support include cellulose acetate, ethyl cellulose, polyethylene terephthalate (PET), plastic vinyl acetate-vinyl chloride copolymer,
Examples include nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polypropylene, polyvinylidene chloride, and aluminum.
These are used, for example, as a single-layer sheet (film) or a laminate of two or more layers. Materials other than aluminum may be used as a woven or nonwoven fabric.

The thickness of the adhesive base layer depends on the flexibility of the patch,
It is related to the adhesive strength of the obtained adhesive base layer. When applied to human skin, the adhesive base layer must have a thickness of at least 10 μm, and preferably at least 20 μm, in order to impart sufficient adhesive strength. On the other hand, when the thickness of the adhesive base layer increases, the drug utilization decreases due to a decrease in the drug concentration and a decrease in the moving speed of the drug to the surface of the adhesive base layer. In addition, when produced by the solvent method, the residual solvent increases, the skin irritation worsens, and causes irritation. For this reason, the thickness of the adhesive base layer is 200 μm or less, preferably 100 μm or less.

[0017]

EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited to the examples. (Examples 1 to 8) 4-amino-3,5- which is a medicinal ingredient
Dichloro-α-[((1,1-dimethylethyl) amino) methyl] benzenemethanol is 1% by weight, and a styrene-isoprene-styrene block copolymer (Shell. 52-54% by weight of Japan (trade name: Clayton D-1107), hydrogenated rosin ester (trade name of Arakawa Chemical Industries KE-
311) at 37-45% by weight, isopropyl myristate (IPM), N-methyl-2-pyrrolidone (NM
P), oleyl alcohol (OA), liquid paraffin (LP), sorbitan monooleate (SO-10),
POE trioleate (20) sorbitan (TO-3
0), patches of Examples 1 to 8 which were prepared by dissolving a composition obtained by appropriately selecting and adding crotamiton (Crota) and diethyl sebacate (DES) to a PET film so as to have a thickness of about 40 μm. Get.

[0018]

[Table 1]

The amount of 4-amino-3,5-dichloro-α-[((1,1-dimethylethyl) amino) methyl] benzenemethanol, which is a medicinal ingredient, was defined as 1% by weight, and the following Table 2 was used.
As shown in the above, instead of the (AB) nA type elastic polymer and the hydrogenated rosin ester, 69.5 to 99% by weight of an acrylic pressure-sensitive adhesive was selected, and isopropyl myristate (IPM), N Methyl-2-pyrrolidone (NM
P), oleyl alcohol (OA), liquid paraffin (LP), sorbitan monooleate (SO-10),
POE trioleate (20) sorbitan (TO-3
0), patches of Comparative Examples 1 to 12 which were prepared by dissolving a composition obtained by appropriately adding and adding crotamiton (Crota) and diethyl sebacate (DES) to a PET film so as to have a thickness of about 40 μm. Get.

[0020]

[Table 2]

The amount of 4-amino-3,5-dichloro-α-[((1,1-dimethylethyl) amino) methyl] benzenemethanol, which is a medicinal ingredient, was set to 1% by weight, and the following Table 3 was used.
As shown in the above, instead of the (AB) nA type elastic polymer and the hydrogenated rosin ester, silicone-based pressure-sensitive adhesives 69.5 to 9
9.0 weight%, isopropyl myristate (IPM), N-methyl-2-pyrrolidone (NMP),
Oleyl alcohol (OA), liquid paraffin (L
P), sorbitan monooleate (SO-10), POE trioleate (20) sorbitan (TO-30),
Crotamiton (Crota), diethyl sebacate (D
After dissolving a composition to which ES) was appropriately added, the patches of Comparative Examples 13 to 24, which were applied to a PET film so as to have a thickness of about 40 μm, were obtained.

[0022]

[Table 3]

(Test Method 1) In Vitro Skin Permeation Test First, each tape preparation according to Examples 1 to 8 and Comparative Examples 1 to 24 of each preparation was used as a sample piece as follows.

A performance test was performed on these sample pieces by the following method. First, a Franz-Improved diffusion cell (1) shown in FIG. 1 was prepared. The diffusion cell (1) comprises a lower cylindrical receptor tank (2) with a bottom and a cylindrical donor tank (3) disposed thereon. An upper flange (4) and a lower flange (5) are superposed on the lower end of the donor tank (3) and the upper end of the receptor tank (2), respectively, so that the donor tank (3) and the receptor tank (2) are overlapped. Are airtightly and concentrically stacked. A laterally protruding sampling port (6) is attached to the side of the receptor tank, and a magnet stirrer (10) is placed inside the receptor tank (2).

Immediately after a hairless rat (8-week-old, male) was sacrificed by cervical dislocation, the abdominal skin was immediately peeled off to remove subcutaneous fat and muscle layer, thereby obtaining a skin piece. This skin piece (11)
Was sandwiched between the upper flange (4) and the lower flange (5) of the diffusion cell (1) so that the space between the donor tank (3) and the receptor tank (2) was completely closed. At this time, the skin piece (11) was set such that the epidermis side was set to the donor tank side and the dermis side was set to the receptor tank side, and water at 37 ° C. was inserted into the jacket (7) via the jacket inlet (8) and the jacket outlet (9). Was circulated from the thermostat.

The sample piece was pressed against the epidermis side of the skin piece (11), the receptor bath was filled with water at 37 ° C., and the receptor solution was stirred by a magnet stirring device. Over the 24 hours after the start of the test, 0.5 ml of the receptor solution was sampled from the sampling port (6) every required time, and immediately thereafter, 0.5 ml of a new receptor solution was replenished. The amount of the present medicinal component contained in the collected receptor solution was measured by high performance liquid chromatography. The number of samples of each patch was three. Based on the measured amount of the active ingredient, the steady state unit area skin permeation rate (Flu
x) was calculated, and the flux value was divided by 5 for conversion to human skin, and the resulting value was converted to the steady state unit area skin permeation velocity (Flux ') for human skin. Steady-state unit area skin permeation rate (Flux) of the medicinal component of each sample of Examples and Comparative Examples with respect to rat skin, and steady-state unit area skin permeation rate (Flux ') in terms of human skin.
And the 24-hour cumulative transmission amount Q are shown in the lower part of each table.

(Test Method 2) With respect to the sample pieces prepared in each of the examples and comparative examples, a sensory test was performed on the adhesiveness and the plaster strength based on the following criteria.
The results are as shown in the lower part of each table. Evaluation Criteria Adhesiveness : The situation when the sample pieces according to the examples and comparative examples were applied to the skin for 1 hour and then peeled was weak: ×, too strong (pain when peeled): Δ, good: ○ . Plaster strength : The condition that the base and the like remain on the skin after the sample pieces according to the present example and the comparative example are stuck to the skin for about one hour. The base remains on the skin: ×, stringing occurs: Δ, Base does not remain on skin: O was evaluated.

As is clear from the comparison of the test results in the lower part of Tables 1, 2 and 3, the sample pieces of each example exhibited superior skin permeability as compared with the sample pieces of the comparative example. N-methyl-2-pyrrolidone as an additive also functions as an element that reduces the steady-state unit area skin permeation rate (Flux), while liquid paraffin, crotamiton, oleyl alcohol, isopropyl myristate, and diethyl sebacate are used as additives. It was found that it functions as an element for increasing the area skin permeation rate (Flux). In particular, oleyl alcohol and isopropyl myristate are elements that function as elements that increase the steady-state unit area skin permeation rate (Flux).

As a result of the transmission test of Examples 1 to 8, S
Since the use of an IS-based adhesive was found to be superior, the factors that increase the skin permeation rate, the factors that decrease the skin penetration, the relationship between the compounding amount of the active ingredient and the compounding of SIS, and the coating on the PET film. Clayton D-1107 (SIS-1) manufactured by Shell Japan Co. and Clayton D-1111 (SIS-2) 23 manufactured by Shell Japan Co., Ltd.
To 46% by weight, hydrogenated rosin ester is 0 to 33.5.
Weight% (referred to as rosin), polyterpene resin (trade name of Yashara Chemical: "Clearon K100" (referred to as K100), alicyclic saturated hydrocarbon resin Alcon P100 (AL)
Isopropyl myristate (IPM), N-methyl-2-pyrrolidone (NMP), oleyl alcohol (OA), liquid paraffin (LP), crotamiton (C
rota), diisopropyl adipate (referred to as DIA), liquid isoprene rubber (referred to as LIR-50), diethyl sebacate (DES), sorbitan monooleate (SO-10), POE trioleate (20) sorbitan (TO) -30), POE (5) hydrogenated castor oil (H
CO-5), POE (20) hydrogenated castor oil (HCO
-20), POE (100) hydrogenated castor oil (HCO-1
00), polyethylene glycol monostearate
(4EO) (MYS-4), polyethylene glycol monostearate (10EO) (MYS-10), polyethylene glycol monostearate (55EO) (MYS-55), polyoxyethylene (2) cetyl Ether (below
BC-2), polyoxyethylene (5.5) cetyl ether (hereinafter referred to as BC-5.5), polyoxyethylene (15.
5) Examples 9 to 47 having compositions shown in Tables 4 to 7 to which cetyl ether (hereinafter referred to as BC-15TX) was appropriately added were prepared, and the same test method as described above was performed on these sample pieces. A test was conducted on the steady-state unit area skin permeation rate (Flux), 24-hour cumulative permeation amount, adhesiveness and plaster strength of the medicinal component of each sample piece. The results shown were obtained. As a result of the steady-state unit area skin permeation rate (Flux), when the present medicinal component is 0.1% by weight (Example 14), the steady-state unit area skin permeation rate (Flux ') in terms of human skin is:
It dropped to 0.05 μg / cm ² / hr, but it was found that when it was 0.5% by weight or more, it fell within a desired range.

[0030]

[Table 4]

[0031]

[Table 5]

[0032]

[Table 6]

[0033]

[Table 7]

(Test Method 3) A skin permeation test was performed using human skin for Example 43 and Comparative Example 11 in the same manner as in Test Example 1 to determine the steady-state unit area skin permeation rate (Flux) in rat skin. The differences were compared.

FIG. 2 is a graph showing the permeation rate of the medicinal component over time in each sample piece. As is clear from these graphs, the sample piece 11 of Example 43 showed excellent skin permeability as compared with the sample piece of the comparative example, and the effective administration area was 0.5 to 10 cm.
^When it is set to ² , the sample of Example 43 is in the required transmission speed range, but the comparative example is less than the required skin transmission speed. As described above, the steady state skin permeation rate of the drug in rat skin and human skin is as follows. Subject agents rats Flux _a person skin skin Flux _b Flux _a / Flux _b Comparative Example 11 0.47 0.07 6.71 Example 43 3.53 1.20 2.98 The obtained results, human skin is not easily transmitted as compared to the skin of rats, the present For drugs, it is 1 / 6.71 to 1 / 2.98,
The fact that rat skin had higher flux than human skin was confirmed. Then, the ratio of the skin permeation rate of the human skin obtained here was applied to the Flux value of the other Examples and Comparative Examples using one fifth of the rat as the conversion rate, and approximated. 'Value.

(Test Method 4) In Vivo Transdermal Administration Test (Single Administration) First, a sample of each preparation was prepared as follows in Example 43.
The preparation of Comparative Example 11 was cut into a size of 10 cm ² to obtain a sample piece.

Performance tests were performed on these sample pieces by the following method. On the day before administration, each sample was applied to the abdomen on a hairless rat (10-week-old, male) whose abdomen was clipped with a hair clipper, the sample was covered with gauze, and fixed with a retaining tape. Peeled off.
250 μL of blood was collected from the jugular vein over time until 48 hours after the start of application of each sample strip, and the amount of the medicinal component in the plasma was measured by high performance liquid chromatography. The number of samples for each patch was three.

FIG. 3 is a graph showing changes in the blood concentration of the medicinal component in each sample. As is clear from this graph, the examples reflected the results of the in vitro skin permeation test in the comparative examples.

[0039]

EFFECT OF THE INVENTION The transdermal patch of the present invention comprises a medicinal ingredient 4-amino-3,5-dichloro-α-
[((1,1-Dimethylethyl) amino) methyl] benzenemethanol or its hydrochloride is (AB) n-A
Is contained in an adhesive base layer mainly composed of an elastic polymer, the effective administration area is 0.5 to 10 cm ² , and the flux ^ss value of the medicinal component is in a specific range. After being absorbed and the blood concentration slowly increases, a stable blood concentration is maintained and the drug effect is continuously exhibited. In addition, it is also possible to avoid side effects of the digestive system that can occur during oral administration and side effects that can occur with a rapid increase in blood concentration.

[Brief description of the drawings]

FIG. 1 is a front sectional view of a Franz improved cell used in a skin permeation test of the present invention.

FIG. 2 is a graph showing the time-dependent permeation rate of the medicinal component of each sample piece for Example 43 and Comparative Example 11.

FIG. 3 is a graph showing the time-dependent change in the plasma concentration of the pharmaceutically active ingredient of each sample piece in Example 43 and Comparative Example 11.

[Explanation of symbols]

 3 Donor 4 Upper flange 5 Lower flange 6 Sampling port 7 Jacket 8 Jacket inlet 9 Jacket outlet 10 Magnet stirrer 11 Skin piece

Claims (4)

[Claims] 1. A medicinal component 4-amino-3,5-dichloro-α-[((1,1-dimethyl) amino) methyl] benzenemethanol is converted to an (AB) n-A type elastic polymer [wherein A is substantially a monovinyl-substituted aromatic compound polymer block, B is a substantially conjugated diolefin polymer block, and n is an integer of 3 to 7]. Steady state unit area skin permeation velocity Flux
^ss (Equation 1) is in the range of 0.15 to 4.0 μg / cm ² / hr in terms of human skin, and the effective administration area of the adhesive base is 0.5 to 10 cm ^2.
A transdermal patch, characterized in that: (Equation 1) 2. The composition according to claim 1, wherein the (AB) nA type elastic polymer of the adhesive base component is a styrene-butadiene-styrene block copolymer or a styrene-isoprene-styrene block copolymer. The transdermal patch of any of the preceding claims. 3. The adhesive base component contains a fatty acid ester (having 7 or more carbon atoms) and / or an aliphatic alcohol (having 7 carbon atoms).
The transdermal patch according to claim 1 or 2, wherein the patch comprises a nonionic surfactant and / or a nonionic surfactant, and contains substantially no filler and no organic acid. 4. The transdermal absorption type according to claim 1, wherein an oleyl alcohol of a higher aliphatic alcohol and / or isopropyl myristate of a higher fatty acid ester are added as essential components to the adhesive base component. Patch.