JPH08127531A - Substrate for percutaneously administering medicine - Google Patents

Abstract

PURPOSE: To obtain the subject substrate developing no medicinal infiltration and diffusion, and excellent in flexibility. CONSTITUTION: This substrate for percutaneously administering medicine consists of a laminated film made up of a barrier film of 1-10μm thick and a flexible film of 50-200μm thick with the surface of the barrier film side formed bellows- fashion.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a support for transdermal drug administration, which is excellent in flexibility and drug permeation / diffusion prevention property.

[0002]

2. Description of the Related Art A drug for transdermal administration comprises a drug contained in an adhesive layer, and the adhesive layer is coated on a support. This transdermal drug is used for the purpose of treatment by applying it to the skin, mucous membranes, etc. and absorbing the drug directly from the skin, mucous membranes, etc., for example, anti-inflammatory analgesics, skin disease tapes, antipruritic patches, wounds. Widely used as an agent. These have been used as local therapeutic agents, but recently they have been used as a systemic therapeutic night unit in the transdermal therapeutic system (TTS).
Has come to be developed.

Examples of such applications include motion sickness agents, anginal agents, and menopausal agents. Due to the widespread therapeutic scope, the demands on the support used for transdermal drug delivery are increasing. Particularly important qualities required for a transdermal drug support are flexibility and the ability to prevent drug penetration and diffusion.

Flexibility is related to the familiarity with the skin,
A product using a support lacking this is liable to peel off, and when peeled off from the skin, stress concentration is apt to occur, causing not only severe pain but also damage to the skin. When diffusion and penetration of the drug occurs, the support swells,
There is a drawback that the amount of drug in the adhesive decreases and the desired therapeutic effect is impaired.

[0005]

Examples of the currently used supports for medicinal preparations for transdermal administration include soft polyvinyl chloride film, polyethylene film, polyethylene terephthalate film, polyurethane film, aluminum vapor deposition film, non-woven fabric, and woven fabric. be able to. this house,
Soft polyvinyl chloride film, polyurethane film,
Polyethylene films and the like are excellent in flexibility, but have drawbacks such as easy penetration and diffusion of drugs. On the other hand, polyethylene terephthalate film, aluminum vapor-deposited film and the like are excellent in preventing drug diffusion and penetration, but have drawbacks such as poor flexibility.

Japanese Patent Publication No. 5-65486 discloses a thickness of 1
Although a support for transdermal drug delivery is disclosed in which a flexible polyurethane-polyvinyl chloride graft polymer film having a thickness of 50 to 150 μm is adhered to a polyethylene terephthalate film having a thickness of 0 μm or less, the flexibility is insufficient.

In view of the above, it is an object of the present invention to provide a support for transdermal drug administration which is free from permeation and diffusion of the drug and is excellent in flexibility.

[0008]

The gist of the present invention is a laminated film in which a transdermal drug carrier is bonded to a barrier film having a thickness of 1 to 10 μm and a soft film having a thickness of 50 to 200 μm. The barrier film side surface is formed of a bellows structure.

The barrier film is, for example,
Polyethylene terephthalate, polyacrylonitrile,
Examples thereof include nylon 6, nylon 66, aromatic nylon, polyvinyl alcohol and the like. Among them, 10
Polyethylene terephthalate (PET) is preferable because a thin film having a thickness of μm or less can be easily obtained. As the polyethylene terephthalate, a biaxially stretched film having a glass transition temperature of 70 ° C. or higher is used. The barrier film can be produced by an existing method such as biaxially stretching a sheet formed by an extrusion method.

The barrier film has a thickness of 1 to 10 μm.
m. If it is less than 1 μm, the drug transfer preventive property is poor and 10
When the thickness exceeds μm, the flexibility is insufficient, so the range is limited. More preferably, it is 1.5 to 8 μm.

Examples of the soft film include soft polyvinyl chloride (soft PVC), polyurethane, low density polyethylene, polyolefin elastomer, and soft polyurethane-polyvinyl chloride graft copolymer (PU-).
PVC) etc. can be mentioned. Of these, soft polyvinyl chloride and soft polyurethane-polyvinyl chloride graft copolymers are preferable because of their good flexibility and strength.

As the soft polyvinyl chloride, it is preferable to add 40 to 100 parts by weight of a plasticizer to 100 parts by weight of polyvinyl chloride resin having an average degree of polymerization of 600 to 2000. The soft polyurethane-polyvinyl chloride graft copolymer has a hardness of 60 to 100 degrees (JIS-
Those of A) are preferred. A plasticizer may be used when more flexibility is required. In this case, PU-PVC100
30 parts by weight or less of the plasticizer is preferable with respect to parts by weight.

The thickness of the soft film before the bellows processing is
It is 50 to 200 μm. If it is less than 50 μm, it is thin and lacks strength and does not function as a support, and if it exceeds 200 μm, it lacks flexibility, so it is limited to the above range. More preferably, it is 60 to 160 μm. The soft film can be produced by an existing method such as an extrusion method or a calendar roll method.

The laminated film according to the present invention can be obtained by coating one side of the barrier film with an adhesive so as to have a thickness of 1 to 10 μm after drying, and laminating and bonding with the soft film. it can. The adhesive is not particularly limited, and examples thereof include polyurethane-based, polyester-based, and acrylic-based adhesives.

The support for transdermal drug delivery of the present invention is a rubber roll in which the above laminated film is heated to 180 to 250 ° C., and the surface on the side of the barrier film is engraved in a shape opposite to the predetermined shape. It can be obtained by pressurizing between and processing into a bellows structure. The engraving depth is about 5 times the depth of the bellows. Since the depth of the bellows structure is also affected by the pressure and temperature at the time of pressurization, the depth of the bellows is controlled to a predetermined depth by controlling the depth, pressure and temperature of the engraving.

The transdermal drug carrier of the present invention has a bellows structure as shown in FIG. 1 on the entire side of the barrier film layer, and a part or all of the cross section in both the longitudinal and transverse directions of the film is
It is preferable to be as shown in FIG. When processed in only one direction, flexibility is obtained only in one direction, and the two-dimensional movement of the skin cannot be followed.

The depth (d) of the valley of the bellows structure is 3 times or more the thickness (a) of the barrier film and 0.9 times or less the thickness of the soft film. (D) is (a)
If it is less than 3 times, the flexibility is insufficient, and if it exceeds 0.9 times the thickness of the soft film, the film in the valley portion becomes thin and the strength becomes insufficient, which is not preferable.

The width (b) of the peak of the bellows structure is 0.2 to
It is 5 mm, and the width of the peak does not have to be constant. If (b) is less than 0.2 mm or more than 5 mm, flexibility is insufficient. More preferably, it is 0.3 to 4 mm. The valley width (c) of the bellows structure is 0.2 to 5 mm, and the valley width may not be constant. If (c) is less than 0.2 mm or more than 5 mm, flexibility is insufficient. More preferably, it is 0.3 to 4 mm.

In the above bellows structure, the area of the peaks is 25 to 400% of the area of the valleys. 25%
If it is less than 400% or more than 400%, flexibility is insufficient. More preferably, it is 30 to 350%.

FIG. 2 shows a pattern example of the cross-sectional shape of the bellows structure. In FIG. 2, as in (1) to (4), the peaks and valleys may be sharp or flat. The widths of peaks and valleys in the case of flatness are shown in (4). Further, it may have a discontinuous structure as shown in FIG.

The support for transdermal drug delivery of the present invention can be used as a transdermal drug by coating a pressure-sensitive adhesive to which a drug is added on the surface on the side of the barrier film processed into a bellows structure.

The drug is not particularly limited as long as it is percutaneously absorbed into the body and exerts a pharmacological effect. For example, anti-inflammatory agents, analgesics, local stimulants, antihistamines, local anesthetics, blood circulation. Examples thereof include accelerating agents, hypnotic sedatives, tranquilizers, antihypertensive agents, antibacterial agents and coronary vasodilators. At least one of these can be selected and used according to the purpose of treatment.

The above-mentioned anti-inflammatory agent and analgesic agent are not particularly limited, and examples thereof include indomethacin, ketoprofen, flurbiprofen, salicylic acid monoglycol ester, and methyl salicylate.

The coronary vasodilator is not particularly limited, and examples thereof include nitroglycerin, nitroglycol, pentaerythritol tetranitrate, isosorbide dinitrate and the like. The antihistamine is not particularly limited, and examples thereof include diphenhydramine hydrochloride, isothibenzyl hydrochloride, and chlorpheniramine.

The polymer used as the main component of the pressure-sensitive adhesive is not particularly limited, and examples thereof include natural rubber, polyisoprene, polyisobutylene, silicone rubber, styrene-
Examples thereof include isoprene block copolymer, acrylic acid ester, methacrylic acid ester and the like. Further, as an additive, a tackifier, a softening agent, a filler, an antioxidant and the like may be added.

As a method for applying the pressure-sensitive adhesive containing the above-mentioned drug, a method of dissolving in a solvent and coating and then drying, a method of melting and extruding into a sheet form from an extruder, and the like can be used. By these methods, the support may be directly coated, or the release paper may be coated and then bonded to the support.

[0027]

EXAMPLES The present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.

Example 1 PET was used for the barrier film layer. The film is produced by biaxially stretching a sheet formed by an extruder.
It was made to be 5 μm. PU-PVC was used for the soft film. As PU-PVC, Dominus K-650F (manufactured by Tosoh Corporation) having a hardness of 65 degrees (JIS-A) was used. PU-
1.5 parts by weight of Ca-Zn stabilizer was added to 100 parts by weight of PVC, and a 100 μm film was formed by a calendar roll. A urethane-based two-component adhesive was applied to the PET film so as to have a thickness of 1 μm after drying, and this was adhered to a soft film to obtain a laminated film. The urethane two-component adhesive is 100 parts by weight of UD417 (solid content 25%, manufactured by Seiko Chemical Co., Ltd.) and isocyanato type curing agent U-400.
0 (manufactured by Seiko Chemical Co., Ltd.) was used in an amount of 2 parts by weight.
The PET film surface of this laminated film was heated to 230 ° C., and a pressure of 1000 kg / m was applied between the iron roll and the rubber roll engraved so that the bellows pattern of FIG. Molded into. The dimensions of the bellows structure are shown in Table 1. The support for transdermal drug delivery was molded as described above.

Evaluation (1) Flexibility A tensile test was conducted in accordance with JIS K 6732 “Agricultural polyvinyl chloride film” to measure a 10% modulus. ○ Less than 4.0 N △ 4.0 N or more and less than 4.5 N × 4.5 N or more (2) Strength The tensile rupture strength was measured according to JIS K 6732 “Agricultural polyvinyl chloride film”. ○ 13 N or more △ 11 N or more and less than 13 N × less than 11 N (3) Drug penetration / diffusion prevention property A pressure-sensitive adhesive containing a drug was applied to the bellows-processed side of the support film. The adhesive was prepared according to the following formulation.
100 parts by weight of natural rubber, 1 hydrogenated rosin acid ester
What added 0 weight part was melt | dissolved in toluene so that it might become 20 weight%. Further, salicylic acid monoester glycol was dissolved to be 2% by weight. This drug-containing pressure-sensitive adhesive solution was applied onto release paper so that the thickness was 15 μm after drying, the solvent was dried, and the solution was attached to a support to prepare a transdermal drug. Immediately after preparing the transdermal drug, 4
It was left still at 0 ° C for 3 months. Then, the amount of glycol salicylate in the adhesive was quantified and the remaining amount was examined. ○ 90% or more and 100% or less △ 70% or more and less than 90% × less than 70% Evaluation results are shown in Table 1.

Examples 2 to 10 Transdermal administration was carried out in the same manner as in Example 1 except that the structures shown in I, II and III of FIG. 4 were obtained and the constitutions shown in Tables 1 and 2 were obtained. A medicinal support was obtained. The evaluation results are shown in Tables 1 and 2.

Example 11 PVC as a soft film, 100 parts by weight of polyvinyl chloride resin, 80 parts by weight of polyester plasticizer, and C
A transdermal skin was prepared in the same manner as in Example 1 except that a film having a thickness of 100 μm was prepared using a calender roll by adding 1.5 parts by weight of an a-Zn stabilizer and was used. A medicated support was obtained. The evaluation results are shown in Table 2.

Example 12 A soft film was formed into a film of 100 μm by an extrusion method using polyester-type Elastollan C60AWN (manufactured by Takeda Birdish Urethane Co., Ltd., hardness 63 degrees (JIS-A)) which is a thermoplastic polyurethane. except,
The structure shown in Table 2 was manufactured in the same manner as in Example 1 to obtain a transdermal drug support. The evaluation results are shown in Table 2.

Example 13 A flexible film is made of a polyolefin-based elastomer, Mirastomer 6030N having a hardness of 60 degrees (JIS-A).
(Mitsui Petrochemical Industry Co., Ltd.) and 100 by the extrusion method.
A support having a structure shown in Table 2 was manufactured in the same manner as in Example 1 except that a film having a thickness of μm was obtained, to obtain a support for transdermal administration. The evaluation results are shown in Table 2.

Comparative Examples 1 to 9 Supports for transdermal drug administration were prepared in the same manner as in Example 1 with the structures shown in I and III of FIG. 4 to have the structures shown in Tables 3 and 4. Got the body The evaluation results are shown in Tables 3 and 4.

Comparative Example 10 Using PVC as a soft film, 100 parts by weight of polyvinyl chloride resin and 35 parts by weight of polyester plasticizer Ca-
A substrate having a structure shown in Table 4 was produced in the same manner as in Example 1 except that 1.5 parts by weight of a Zn-based stabilizer was added to form a 100 μm film with a calendar roll. Obtained. The evaluation results are shown in Table 4.

[0036]

[Table 1]

[0037]

[Table 2]

[0038]

[Table 3]

[0039]

[Table 4]

[0040]

EFFECTS OF THE INVENTION Since the transdermal drug carrier of the present invention has the above-mentioned constitution, it does not swell the support or reduce the amount of the drug in the pressure-sensitive adhesive due to excellent flexibility without penetration and diffusion of the drug. It is possible to provide a transdermal drug that does not easily peel off when applied to the skin and does not damage the skin when peeled off from the skin.

[Brief description of drawings]

FIG. 1 is a schematic cross-sectional view of a bellows structure of a transdermal drug carrier of the present invention.

FIG. 2 is a diagram showing a pattern example of a cross-sectional shape of a bellows structure.

FIG. 3 is a view showing a discontinuous cross-sectional pattern of a bellows structure.

FIG. 4 is a diagram showing a bellows structure of an example. The solid line represents the mountain line and the dotted line represents the valley line.

[Explanation of symbols]

a Barrier film layer thickness b Peak width b ₁ Vertical length b ₂ Horizontal width c Valley width c Valley width c ₁ Valley vertical length c ₂ Valley horizontal length d Valley depth

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[Procedure amendment]

[Submission date] November 10, 1994

[Procedure Amendment 1]

[Document name to be corrected] Drawing

[Name of item to be corrected] Fig. 4

[Correction method] Change

[Correction content]

[Figure 4]

Claims (4)

[Claims] 1. A laminated film obtained by adhering a barrier film having a thickness of 1 to 10 μm and a soft film having a thickness of 50 to 200 μm, wherein the surface on the barrier film side is formed into a bellows structure. Transdermal drug support. 2. The support for transdermal administration according to claim 1, wherein the barrier film is made of polyethylene terephthalate. 3. The soft film comprises a soft polyurethane-polyvinyl chloride graft copolymer, soft polyvinyl chloride,
Polyurethane or polyolefin elastomer 100
The support for transdermal drug administration according to claim 1 or 2, which comprises 40 to 100 parts by weight of a plasticizer in parts by weight. 4. The bellows structure has a valley depth which is 3 times or more the thickness of the barrier film in the longitudinal direction and the transverse direction in a part or all of the cross section of the film, and the thickness of the soft film. The width of the peak and the width of the valley are 0.2 to 5 mm, and the area of the peak is 25 to 400% of the area of the valley. Or the support for transdermal administration as described in 3 above.