JPH0525038A - Agent for transcutaneous absorption - Google Patents

Abstract

PURPOSE:To mitigate the unpleasant feeling, rash, etc., while keeping easy and excellent sustained release effect by using a woven fabric composed of a modified cross-section fiber of especially polyester, polyamide, etc., having a specific diameter as the supporting material for a transcutaneous absorption agent. CONSTITUTION:A woven fabric made of a fiber having a diameter of 1-10mum, especially polyester fiber, polyamide fiber or their mixture having modified cross-section is used as a substrate, which is combined with a base agent layer containing an agent (especially preferably estrogen, luteinizing hormone or their mixture). The substrate is preferably heat-treated on at least one surface. The agent can control of the release of an agent for the treatment of the climacteric disturbance of postmenopausal woman, osteoporosis, Alzheimer's dementia, etc., mitigate the disagreeable feeling to the skin and reduce the side effects such as rash and stuffing of the skin caused by the application over a long period.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a percutaneous absorption preparation excellent in feeling of use and free from skin irritation or rash. More specifically,
In a percutaneous absorption preparation comprising a support and a base layer containing a drug, by using a woven fabric made of fibers having a diameter of 1 μm or more and 10 μm or less for the support, a simple and excellent sustained release effect can be obtained. On the other hand, discomfort when applying and skin irritation,
The present invention relates to a patch preparation for transdermal administration capable of reducing side effects such as stuffiness.

[0002]

Conventionally, the skin has been often used as a drug application site, but it was only intended for local treatment such as sterilization and inflammation of the skin surface. However, in recent years, the skin has attracted attention as an application site of drugs intended for systemic effects as well as local effects. The reason for this is that transdermal preparations have an administration site on the surface of the body compared to oral preparations and injections, which makes administration easier. By controlling the amount and rate of release, it is possible to maintain a constant blood concentration, which makes it possible to achieve sustained or rapid-acting. Avoid metabolism in the liver. It is possible to avoid gastrointestinal disorders, pains and tissue disorders caused by injections, which are problems with oral administration. This is because it has advantages such as.

However, depending on the application purpose of the drug, the number of administration days may be 2 to several days, and the period of use may reach several years, which is insufficient for patient compliance. It has become possible to be. Hereinafter, description will be made by taking an estrogen preparation as an example. Recently, reduction of estrogen (estrogen) has been emphasized as a cause of menopausal disorders, osteoporosis, and Alzheimer-type dementia in postmenopausal women. Therefore, administration of estrogen is carried out for these treatments, but when it is orally administered, it is said to have a bioavailability of 50% or less because it is immediately metabolized in the liver. , In addition,
Side effects such as gastrointestinal disorders also occur, which is not desirable for treatment. In addition, when administered by injection, the blood concentration is significantly higher than the physiological level, but the action is transient and does not last for a long time, so it is necessary to frequently administer the drug. Furthermore, overdose of estrogen also causes endometrial cancer.

These problems can be solved by transdermally absorbing estrogen. That is, since the drug can be sustainedly released by using the percutaneous absorption preparation, the bioavailability can be improved, and in addition, the blood concentration can be controlled to be constant. Many such attempts have already been disclosed. For example, in JP-A-57-154122,
Multilayered transdermal formulations are disclosed. In this, a drug absorption enhancer layer, a diffusion film layer and a pressure-sensitive adhesive layer are sequentially laminated on a film-like support, and the drug release rate is controlled by the diffusion film layer. In addition, a release rate control method utilizing the diffusion rate of a drug, which comprises an impermeable film support, a silicon matrix layer in which the drug is dispersed, and an adhesive layer in which an absorption promoter is mixed (Japanese Patent Publication No. 1-501146).
A percutaneous absorption preparation having a pressure-sensitive adhesive layer containing a specific absorption enhancer on a drug-impermeable support or a drug-impermeable support (JP-A-2-196714).
No.), a transdermal drug having an adhesive layer containing polyvinylpyrrolidone together with a drug on a water-impermeable or semi-permeable film (JP-A-3-34923).

However, since estrogen therapy compensates for the decrease in estrogen associated with menopause, the treatment period extends from several months to several years, and therefore high patient compliance is an essential condition. In particular, it is a problem that a large amount of discomfort at the time of application, skin irritation, and swelling occur. All of the above-mentioned disclosed techniques seem to be useful methods for controlling the release of drugs, but it cannot be said that these problems have been sufficiently solved.

Japanese Unexamined Patent Publication (Kokai) No. 2-237926 describes that skin rashes are improved by incorporating a fabric made of hollow fibers into an adhesive layer. However, since the drug is contained in the hollow fibers, the hollow fibers are unnecessarily bulky and the discomfort during application increases. Further, in JP-A-2-240013 and JP-A-2-240014, a specific ethylene
There is a disclosure that by using a sticking base material composed of an ultrafine fiber non-woven fabric made of a saponified vinyl acetate copolymer, it is disclosed that the discomfort during use is reduced, but this one is used as a base material (support). Since a non-woven fabric is used, the thickness of the base material itself increases, which is not suitable for long-term use.

[0007]

As described above, conventional transdermal preparations are superior to oral preparations and injections in controlling drug release, but patient compliance is sufficiently solved. However, there is a problem of discomfort at the time of application and skin irritation and rash during long-term use.

[0008]

In order to solve the above-mentioned problems, the present invention has investigated various kinds of supports for transdermal preparations, and as a result, the supports consist of fibers having a diameter of 1 μm or more and 10 μm or less. It was found that when a woven fabric is selected and used, a patch preparation for transdermal administration, which has a simple and excellent sustained-release effect and reduces side effects such as discomfort during application and skin irritation or rash, The present invention has been completed based on this finding. That is, according to the patch preparation for transdermal administration of the present invention, the fine voids between fibers are increased, as a result, the water permeability is improved, and the occurrence of skin rash and rash can be eliminated, and the support is also provided. It is also possible to reduce the body thickness.

The fibers having a diameter of 1 μm or more and 10 μm or less used for the support of the present invention can be produced by a known technique, and can be made into a woven fabric by a known technique. Further, the fibers may have a circular cross section, or a modified cross section such as a triangle, a quadrangle, a rectangle, an ellipse, or a star.
The material is not particularly limited as long as it is an organic polymer compound, but polyester fibers, polyamide fibers or mixed fibers thereof are preferable.

Further, since these fibers can be easily shrink-processed by heat, they can be processed by heating into a support having a hardness having an appropriate shape-retaining property. Therefore, a substance having a relatively large molecular weight such as a drug does not evaporate, and a support that allows only water to permeate can be obtained. Further, when the fiber has an irregular cross section, it is possible to adjust the permeability by heat-welding a part of the tip of the cross section. In the present invention, the woven cloth means a material obtained by spinning, weaving or braiding fibers.

As the drug used in the drug-containing base layer of the present invention, any drug can be used as long as it is applicable to transdermal administration, and in particular, estrogen, luteinizing hormone, or a mixture thereof is used. preferable. Examples of the estrogen include 17β-estradiol or its ester, ethinyl estradiol or its ester, estriol or its ester, or a bound estrogen. Moreover, progesterone, chlormadinone acetate, hydroxyprogesterone acetate, dihydrogesterone, allylestrenol,
Examples thereof include norethisterone, hydroxyprogesterone or esters thereof. The content of these drugs is
It is appropriately determined to suit the patient's condition. Although estrogen may be used alone, it is preferably used in combination with progesterone in the sense of preventing the action of inducing endometrial cancer.
The ratio of estrogen and progesterone is 1: 1 because progesterone is less active and has a faster metabolic rate.
-1: 100 is preferred.

The base layer of the present invention may contain an adhesive, which is not particularly limited as long as it can adhere to the skin for the time required for administration, and preferably an acrylic adhesive such as acrylic. A copolymer of 2-ethylhexyl acid and vinylpyrrolidone can be mentioned. Further, a drug absorption enhancer may be used in the base layer of the present invention, and may be added to the drug in advance or may be added when the base layer is prepared.
As the absorption promoter, known propylene glycol, glycerin, fatty acids or alkali salts thereof, and fatty acid esters can be used. Further, in the base layer, a release sheet layer may be formed on the contact surface with the skin, and for example, a silicone-coated release sheet is used. Such a release paper is used for protecting the base layer until use.

The percutaneous absorption preparation of the present invention can be produced, for example, as follows. First, dilute the adhesive with a suitable solvent,
To this, a drug and, if necessary, an absorption enhancer are added and mixed uniformly. The obtained solution is applied to the surface of the support and dried. Alternatively, it is also possible to apply this solution on a silicone-coated release paper, dry it, and then bring it into close contact with the support.

[0014]

EXAMPLES Next, examples, comparative examples and experimental examples will be given.
The present invention will be described in more detail but is not limited thereto.
Not a thing.Example 1 2-Ethylhexyl acrylate: 65 mol, vinyl pyro
Redone: 35 mol and hexamethylene glycol dime
Ethyl acetate added to tacrylate (0.02% by weight based on total weight)
To give a monomer concentration of 85% by weight,
Add a small amount of lauroyl chloride and in nitrogen gas at 60 ° C for 30 hours
The mixture is heated for a period to obtain a polymer solution. Obtained polymer solution 10
A methanol solution of estradiol was added to 0 part (0.5 part: 1
0 parts) 10 parts and 5 parts propylene glycol
After making the dope uniform, place it on a silicone-coated release paper
And estradiol and dried for 30 minutes at 80 ℃
A layer (adhesive layer) containing an acrylic adhesive was obtained. Dry
The thickness of the later pressure-sensitive adhesive layer was 40 μm. Acquired
Diameter 5μ with triangular irregular cross-section on one side of ril adhesive layer
1: 1 blend of m polyester and nylon
A 50 μm-thick support made of a knitted fabric is pressure-bonded and percutaneously absorbed.
A harvested formulation was obtained. The estradiol content of this product is 4
mg / 10cm²Met.

[0015]Example 2 Made of 5 μm diameter polyester with triangular profile
One side of a 50 μm thick woven fabric heat treated at 180 ° C
The same operation as in Example 1 was carried out using the ground as a support. However,
The pressure-sensitive adhesive layer was pressure-bonded to the surface not subjected to heat treatment.

[0016]Example 3 The procedure of Example 2 is repeated to obtain a polymer solution. Got
100 parts of polymer solution with estradiol and progesterone
Methanol mixed solution (0.3 parts: 1.0 parts: 10 parts) 10
Parts and 5 parts of propylene glycol are added to form a uniform dough.
Then, apply it on a silicone coated release paper,
Dry at 80 ℃ for 30 minutes and estradiol progester
Ron and the layer containing acrylic adhesive (adhesive layer)
It was The obtained acrylic adhesive layer has a triangular cross section on one side.
5μm diameter polyester and nylon with
(Trademark) 1: 1 mixed-spun support having a thickness of 50 μm
Was pressure-bonded to obtain a transdermal preparation.

[0017]Comparative Example 1 38 μm thick polyester film was used for the support
A percutaneous absorption preparation was obtained in the same manner as in Example 1 except for the above.Comparative example 2 The support has a thickness of 50 μm and is made of polyester with a diameter of 15 μm.
The same procedure as in Example 2 was repeated except that a woven fabric of μm was used.
A skin absorption preparation was obtained.Comparative Example 3 The support has a thickness of 50 μm and is made of polyester with a diameter of 15 μm.
The same procedure as in Example 3 was repeated except that a μm woven fabric was used.
A skin absorption preparation was obtained.

[0018]Experimental example 1 The percutaneous absorption preparations obtained in Examples and Comparative Examples were 3 cm.²of
Cut to size and attach to the back of a dehaired male rat 6
Blood was collected at time and 12 hours later, and estradiol and
And progesterone serum concentrations in radioimmunoassay
It was measured by the method. The results obtained are shown in Table 1.

[0019]

[Table 1]   Item Drug concentration   6 hours later 12 hours later   Example 1 Estrogen 600 555   Example 2 Estrogen 585 545   Example 3 Estrogen 350 320             Progesterone 980 850   Comparative Example 1 Estrogen 555 485   Comparative Example 2 Estrogen 490 375   Comparative Example 3 Estrogen 330 290             Progesterone 920 780 No significant difference was found in the drug transfer rate into the blood, but a comparative example
In the case of 2, the concentration of the
A decrease was observed.

[0020]Experimental example 2 Do not use estradiol or progesterone
As in Examples 1 to 3 and Comparative Examples 1 to 3 except
Manipulate the product and cut it into 10 cm x 10 cm plastic
A sevo formulation was obtained. The placebo preparation was applied to the backs of 5 healthy adults.
The condition of the skin when applied on the center and removed 2 days after application
I observed. The results are shown in Table 2.

[0021]

[Table 2]item           Skin condition after removal of patch Example 1 No change Example 2 No change Example 3 No change Comparative Example 1 Redness and itching occur Comparative Example 2 Redness and itching occur Comparative Example 3 Redness and itching occur With the percutaneous absorption preparation of the present invention, the effect on the skin was reduced.
Was not recognized.

[0022]

INDUSTRIAL APPLICABILITY As described above, according to the present invention, the skin permeability of the drug is high, the release amount can be controlled, and the skin disorder such as discomfort or skin irritation or rash even during long-term use. A percutaneous absorption preparation that does not cause

[Brief description of drawings]

FIG. 1 is a cross-sectional view of the transdermal preparation of the present invention, which is the transdermal preparation obtained in Example 1.

[Explanation of symbols]

1: Support (1: 1 mixed spun fabric of polyester and nylon (registered trademark)) 2: Drug-containing base layer (containing estradiol and acrylic adhesive)

Claims (5)

[Claims] 1. A percutaneous absorption preparation comprising a support and a base layer containing a drug, wherein the support is a woven fabric made of fibers having a diameter of 1 μm or more and 10 μm or less. 2. The transdermal preparation according to claim 1, wherein the drug is estrogen, luteinizing hormone, or a mixture thereof. 3. The percutaneous absorption preparation according to claim 1, wherein the fiber has a modified cross section. 4. The percutaneous absorption preparation according to claim 1, wherein the fiber is a polyester fiber, a polyamide fiber or a mixed fiber thereof. 5. The transdermal preparation according to claim 1, wherein at least one surface of the support is heat-treated.