JPS58113275A - Pressure-sensitive adhesive composition - Google Patents

Abstract

PURPOSE:The titled composition that contains a clathrate compound from a substance with the steroid structure, thus showing high physiological activity of steroid with high stability. CONSTITUTION:A substance with the steroid structure such as fluorocinnolone acetonide is made into a clathrate compound using beta-cyclodextrin or gamma-cyclodextrin and the product is combined to produce the objective pressure-sensitive adhesive composition.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pressure sensitive adhesive compositions for adhesive tapes used in therapy.

Traditionally, compounds with a steroid skeleton, such as hydrocortisone, betamethacin and other adrenocortical hormones, testosterone, estrone, phlogestrone and other sex hormones, digoxin, digitoxin and other cardiac glycosides, and bile acids, have strong physiological activity and are important as drugs. Many of them have been used as medicines since ancient times. The molecular weight of these compounds having a steroid skeleton is θo-to.

Domestically and internationally, some hormones are used in the form of ointments, creams, etc. because they are smaller than polypeptide hormones and can be absorbed through the skin.

The present invention provides a pressure-sensitive adhesive containing a steroid compound with good stability and high pharmacological action, by converting a compound having a steroid skeleton into a clathrate compound such as schiflovkis, etc., and incorporating it into a pressure-sensitive adhesive component. The aim is to provide a tape agent.

Cyclodextrin is a ring in which an integral number of glucose units are bonded together to form a ring. α-cyclodextrin consists of 6 glucose groups, and the size of the cavity of the ring is the inner diameter. Also, the depth is 7 A, β-cyclodextrin has 7 glucose groups), and the size of the cavity of the ring is 7 A. OA1 depth is 7.0A,
γ-Cyclodextrin consists of r glucose groups,
The size of the cavity is said to be an inner diameter of ♂, 5k, and a depth of 7.0λ, and other molecules are incorporated into these cavities to form so-called clathrate compounds, but the size of the cavity In the case of steroid compounds, β- and γ-cyclodextrins are preferred, and in the case of β-cyclodextrin, mainly steroid:cyclodextrin=/:
2. In the case of γ-cyclodextrin, it is said that clathrate compounds are mainly formed at a molar ratio of steroid:cyclodextrin=2:3. This steroid
Cyclodextrin clathrate compounds have excellent solubility, release properties, stability, bioavailability, etc., and not only do they require smaller amounts to achieve the same medicinal efficacy than steroid compounds alone, but they can also be applied easily. Undesirable side effects can also be minimized. In addition, steroids such as fludinolone acetonide, betamethacin valerate, and others, which required selection of the pressure-sensitive adhesive components conventionally blended, can be blended as clathrate compounds as described above, so that they can be blended as conventional pressure-sensitive adhesive components. In addition, cardiac glycosides such as digitoxin, which had problems in being incorporated into pressure-sensitive adhesive components due to release properties, can be incorporated into pressure-sensitive adhesive components by making them into clathrate compounds. It is now possible to combine For example, the MCKenzie skin pallor index, which indicates the strength of the adrenocortical hormone, of the fluoronolone acetonide is /θ0, but if this is added to the pressure-sensitive adhesive component (= blended to make a tape), the pallor The pallor effect is weaker than a tape containing the same amount of fludroxycortide, which is a weaker adrenal corticosteroid with a weaker whitening index.For this reason, it contains fludrocortide, which has a lower pallor index, than μflea. In order to obtain a tape with a pallor effect equivalent to that of the tape, the content of fludinolone acetonide should be increased by approximately 2.
Double! μ? /crA. This is due to the difficulty in releasing fluocinolone acetonide from the tape, but if this fluocinoconvex acetonide is blended as a clathrate compound of the β-cyclodextrin, it contains almost the same amount as fludroxycortide. amount (μt/
It was found that similar medicinal effects could be obtained using di).

In addition, there are cardiac glycosides 1 for the treatment of diseases such as heart failure, myocardial infarction, and arrhythmia, such as digitalis drugs. Digitalis drugs mainly use digitoxin and digoxin, and are usually administered intravenously or orally to reduce the concentration in the blood to a toxic level. In order to suppress the amount to the so-called saturation amount (approx. Digitalis agents can be replenished transdermally using a tape containing the digitalis agent in a pressure-sensitive adhesive; it has been said that it is difficult to absorb these agents, but these digitalis agents can be replenished with cyclodextrin, etc., as described above. An example in which it was found that transdermal absorption could be easily achieved by using a tape formulation formulated as a compound / β-cyclodequinutrin 2.2♂f<2×10=mol)
into water, fOml, and heated to about 7θ℃ to dissolve,
To this, 0.22t3t(θ,
tX/0-3 mol) in acetone! After stirring and cooling for about 5 hours, the separated precipitate was dried to form a cyclodextrin clathrate compound of dinolone acetonide/? , < f was obtained. This clathrate /, 0
f for acetone! Dispersed in θ-, coethylhexyl acrylate, weight it%, vinyl acetate weight type, acrylic acid! Ethyl acetate/toluene (9:/) solution of acrylic copolymer consisting of weight ratio (contains solid content, 23%, 3%)
Solution viscosity at 0°C: 2 poise)
The mixture was thoroughly stirred for a long time to form a sticky liquid. This adhesive liquid was applied onto a silicone-treated release paper so that the thickness after solvent volatilization was 0μ, the solvent was volatilized at room temperature, and the nail was heated at 100°C for 7 minutes to completely volatilize the solvent. , thickness 700
A piece of polyethylene adhesive tape containing full-sided dinolone acetonide was obtained by laminating it on the corona-treated surface of a soft polyethylene film that had been subjected to matte treatment on one side and corona treatment on one side. Cut this tape piece into 2yd, remove the release paper, and
Shake for 30 minutes in 0-methanol and repeat this extraction three times to obtain a total of 30 ml of extract, which was passed through a silica gel column (Florisil) to remove impurities from the adhesive, dried, and used as an eluent. Methanol: Water (, <:
When high-performance liquid chromatography (column 2 μm Pondapak C-/♂) was analyzed using 2 μm column g), the fluocinolone acetonide content was 99.0 μf/cdl.
It was a male.

In order to compare the medicinal efficacy of this tape preparation, the capillary constriction ability was examined in a skin pallor test (2). A test was conducted by adding a commercially available adrenocorticosteroid-containing tape containing fludroxycortide.The test was conducted on 2y healthy subjects.A sample tape with a diameter of /,! was applied to the back of each person, and after the tape was removed,
Time, 9 hours? Examine the degree of skin pallor after an hour.
The results are shown in Table/.

Table / However, FA: fluocinolone acetonide FA-CD: fluocinolone acetonit ° cyclodextrin clathrate compound (drug content is indicated by the amount of fluocinolone acetonide) FC-' Commercially available tape containing brudroki dicortide determination Criteria +... Clear pallor ±... Mild pallor -... No reaction From the results in Table (7) above, in the case of fluocinolone acetonide alone, the content of the male μg shoulder was compared to the control. It appears that the medicinal efficacy is almost the same as that of Fludro Mushroom Curtidog μ2 Shoulder, but Fluocinolone Acetonidog μfAl showed a pallor phenomenon that was clearly inferior to that of the comparison control. However, in the case of fluocinolone acetonide/cyclodextrin clathrate compound, even if the fluocinolone acetonide content is equal to μ2, it is difficult to compare fluocinolone acetonide μt/cd or ♂μ when using fluocinolone acetonide alone. It showed the same or greater pallor compared to AI. From the above results, it has been found that the use of cyclodextrin inclusion compounds is extremely effective in increasing the bioavailability of adrenocortical hormones such as fluocinolone acetonide.

Betamethacin valerate o, :z was prepared in the same manner as in Example.
3ztcθ,! ×/θ−3 mol) β-cyclodextrin clathrate compound 7.3♂2 was obtained. This clathrate compound/
0g to acetone j07! The mixture was added to 922f of silicone adhesive (Dow Corning Co., Ltd. A3!;3;, solid content/!,!% by weight, solvent used: trifluorocarbon) and stirred well for about 9 hours to obtain a sticky liquid. The thickness of the adhesive after solvent volatilization was applied to a soft polypropylene film with a thickness of 10θμ, which had been treated with a matte finish on one side and a corona treatment on the other.
Apply to ioμ, air dry at room temperature, and then heat to 1.10°C.
The mixture was heated for 7 minutes to completely remove the solvent, and then the adhesive surface was covered with wax-treated crepe release paper to obtain an adhesive tape piece containing betamethacin valerate.

The content of betamethacin valerate in the obtained tape piece was determined by treating it in the same manner as in Example/using acetone as an extractant, using water, niacetonitrile, Cso:to>r:μm Bondapak C-
Quantification by high-performance liquid chromatography using /♂ showed that the content was 3 μf/cr/l versus 3 μf/♂. As shown in Table 2, the results of the vasoconstriction test for this tape piece were better than those containing 1&μf/crl that did not use a cyclodextrin clathrate;
/cr/l showed the same or better performance than the comparison control containing μF/, -d without cyclodextrin clathrate, or fludroxycortide μf/cd. Therefore, it is clear that the application of cyclodextrin clathrate compounds to betamethacin valerate is effective in improving the bioappellability, and that a higher effect can be achieved with the use of a smaller amount of drug. By applying this technology, it is possible to tape not only adrenocortical hormones but also useful drugs with steroid skeletons such as cardiac glycosides.

Table 2 below shows the diameter/diameter on each person's back for 2f healthy people.
,! The results were obtained by applying a secondary sample tape and examining the degree of skin pallor in the same manner as in Example.

(Left below) Table 2 Time after tape removal 7 hours 2 hours
However, BMV...Petamethacin valerate BM
V-CD... Betamethacin valerate/cyclodextrin clathrate (drug dosage is as betamethacin valerate) FC... Judgment criteria for commercially available tapes containing fludroxycortide +... Clear pallor ±... Mild pallor - no reaction

Claims (1)

[Claims] / A pressure-sensitive adhesive composition containing a substance having a steroid skeleton as an clathrate compound. The pressure-sensitive adhesive composition according to claim 1, wherein the clathrate is a cyclodextrin clathrate. 3. The pressure-sensitive adhesive composition according to claim 2, wherein the cyclodextrin is β-cyclodextrin. 3. The pressure-sensitive adhesive composition according to claim 2, wherein the cyclodextrin is γ-cyclodextrin.