JP3302822B2 - Transdermal drug support - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a support for a drug for transdermal administration having a drug transfer preventing property.

[0002]

2. Description of the Related Art Transdermal drugs intended to administer a drug into the body through the skin by being attached to the skin are:
In general, it is also called a patch, and various forms such as cataplasms and plasters have been developed. Transdermal drugs are formed by laminating a pressure-sensitive adhesive layer containing a drug on a support, and the drug to be contained is a local-acting drug such as an anti-inflammatory analgesic or a systemic drug such as a vasodilator. And so on.

[0003] Since the above-mentioned transdermal drug is applied on the skin surface, it must be free from discomfort when applied and follow the movement of the skin, and the support has flexibility. Raw materials, for example, plastic films such as vinyl chloride resins, nonwoven fabrics and woven fabrics are used. In addition, a material having elasticity as well as flexibility is used for a portion where the attachment portion is a bent portion such as an elbow and knee joint portion.

[0004] In the above-mentioned drug for transdermal administration, an amount of the drug necessary for exerting a pharmacological effect must be contained in the pressure-sensitive adhesive layer. The drug contained therein moves to the skin surface and also to the support. The drug migrated into the support diffuses and moves in the support and volatilizes from the back surface of the support, and the drug in the pressure-sensitive adhesive layer decreases with time, which causes a problem that a pharmacological effect cannot be sufficiently exerted.

For example, non-woven fabrics and woven fabrics used as supports are porous, so that sublimable and strongly odorous drugs such as l-menthol and dl-camphor commonly used as analgesic and anti-inflammatory drugs are used. When the drug is used, the drug is released into the atmosphere, and the amount of the drug is reduced. In addition, the drug gives uncomfortable feeling to the user of the transdermal drug and the surroundings, which is not preferable. The plastic film does not have the above-mentioned disadvantage because it has no porosity, but has a property of absorbing a drug and cannot prevent the transfer of the drug from the pressure-sensitive adhesive layer to the support.

As a technique for imparting a drug transfer preventing property to a support, there are a method of laminating a layer having a drug transfer preventing property between a support and an adhesive layer, and a method of providing a support itself having a drug transfer preventing property. There is a method of forming with a thing. As a method of laminating a layer having a drug transfer preventing property, for example, a method of laminating PET on a soft plastic film such as polyvinyl chloride, ethylene-vinyl acetate copolymer, polyurethane, low density polyethylene, ultra low density polyethylene, etc. And a laminate of a fluororesin (JP-A-2-237915) and a laminate of a metal thin film such as an aluminum foil.
In addition, as a method for forming the support itself with a drug transfer preventing property, there is a method using biaxially stretched polyethylene terephthalate as the support. Japanese Patent Application Laid-Open No. Hei 4-298339 discloses a technique using a polyester film having a difference between a cold crystallization temperature and a glass transition temperature of 60 ° C. or less as a support.

However, a laminate of layers having a drug transfer preventing property has problems such as lack of flexibility of the support, lack of elasticity, and easy formation of the formed drug transfer preventing layer. is there. In addition, biaxially stretched polyethylene terephthalate is easily crystallized, has a high elastic modulus and lacks flexibility, and the above-mentioned copolymerized polyester film lacks flexibility because it has crystallinity. Therefore, none of them was a good support.

[0008]

SUMMARY OF THE INVENTION In view of the above, it is an object of the present invention to provide a support for a drug for transdermal administration which has flexibility and drug transfer preventing properties.

[0009]

SUMMARY OF THE INVENTION The gist of the present invention is to provide a medicinal support for transdermal administration on a film made of polyvinyl chloride, polyvinyl acetate, polyurethane or polyolefin and having a thickness of 50 to 180 μm. , 60
An ethylene glycol / neopentyl glycol mixed diol mixed at a molar ratio of 60/40 to 40/60;
A polyester (A) obtained from a terephthalic acid / isophthalic acid mixed dicarboxylic acid mixed in a molar ratio of 40 to 40/60, the mixed diol, and 90/10 to 70 /
Polyester (B) obtained from terephthalic acid / sebacic acid mixed dicarboxylic acid mixed at a molar ratio of 30 and polyester (B) obtained by mixing at a weight ratio of (A) / (B) = 50/50 to 90/10, and having a thickness of 3 ２８28 μm.

[0010] Since the polyester (A) is constituted as described above, it has a low property of absorbing a drug and is excellent in a drug transfer preventing property. Further, since the polyester (B) is constituted as described above, it is amorphous and has sufficient flexibility. In the present invention, the weight ratio between the polyester (A) and the polyester (B) is set to 50/50 to 90/10. 50 / weight ratio
If it is less than 50, it has flexibility but lacks the ability to prevent drug transfer, and if it exceeds 90/10, it has the ability to prevent drug transfer but lacks flexibility, so it is limited to the above range.

The composition of the present invention may contain an isocyanate crosslinking agent for the purpose of increasing the degree of crosslinking. As the isocyanate crosslinking agent, for example, diisocyanate,
Triisocyanate, tetraisocyanate and the like can be used, but triisocyanate is preferred from the viewpoint of improving drug transfer prevention by cross-linking and not significantly reducing flexibility. As the triisocyanate,
For example, triphenylmethane-4 ', 4 ", 4"-
Triisocyanate, tri (isocyanate phenyl)
Examples thereof include thiophosphate, an adduct of trimethylpropanol-tritoluene diisocyanate, and an adduct of trimethylpropanol-trihexamethylene diisocyanate.

The above isocyanate crosslinking agent is a composition 100 comprising a polyester (A) and a polyester (B).
Add 0 to 10 parts by weight based on parts by weight. If the amount exceeds 10 parts by weight, the flexibility is insufficient, so that the content is limited to the above range.
It is preferably at most 8 parts by weight.

[0013] In the present invention, the above composition has a thickness of 3 to
Laminate to 28 μm. If it is less than 3 μm, the drug migration-preventing properties will be insufficient, and if it exceeds 28 μm, the flexibility will be insufficient. Preferably it is in the range of 5 to 25 μm.

In the present invention, a film made of a polyvinyl chloride-based, polyvinyl acetate-based, polyurethane-based or polyolefin-based plastic is used as a film for laminating the above composition. The above-mentioned film is usually used as a soft film and as a support of a drug for transdermal administration.

In the present invention, the thickness of the plastic film is in the range of 50 to 180 μm. 50μ
If it is less than m, it is too thin to be inconvenient to handle, and if it exceeds 180 μm, it is too thick, lacks flexibility, is conspicuous, and has an aesthetic problem, so it is limited to the above range. Preferably it is in the range of 60 to 160 μm.

The support of the present invention is prepared by dissolving the polyester (A) and the polyester (B) in a suitable solvent and mixing them.
After appropriately adding an isocyanate cross-linking agent or the like, it can be produced by a method of coating the above plastic film and drying. The coating can be performed using, for example, a gravure coater, a reverse coater, a micron bar coater, or the like.

[0017]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto. Example 1 Neopentyl glycol, ethylene glycol, terephthalic acid, and isophthalic acid were mixed at a molar ratio of 50: 50: 50: 50.
Was dissolved in a solvent in which toluene / MEK was mixed at a ratio of 4/1 at a solid content of 40% by weight to obtain a polyester (A) solution. Separately,
Byron 300 (manufactured by Toyobo Co., Ltd.) obtained by copolymerizing ethylene glycol, neopentyl glycol, terephthalic acid, and sebacic acid at a molar ratio of 50: 50: 80: 20 was mixed with a toluene / MEK ratio of 4/1 at a solid content of 40% by weight. The polyester (B) solution was dissolved in the solvent mixed in the above.

As a plastic film, suspension polymerization was carried out on polyvinyl chloride having a degree of polymerization of 1050, and as a plasticizer, adipic acid-based polyester 5 having a molecular weight of 2,000 was used.
0 parts by weight, 1 part by weight of a calcium-zinc stabilizer,
1.5 parts by weight of a chelator and 2 parts by weight of epoxidized soybean oil were added, and formed by a calender roll at a temperature of 170 ° C. and having a thickness of 100 μm (hereinafter referred to as “soft PV”).
C film).

A mixture of the polyester (A) solution and the polyester (B) solution in a weight ratio of 70:30 was dried on a soft PVC film having a thickness of 100 μm and dried to a thickness of 15 μm.
m and dried with hot air at 130 ° C. for 2 minutes to obtain a laminated support. 100 parts by weight of a styrene-isoprene-styrene block copolymer (Califlex TR1107 manufactured by Shell Chemical Company),
80 parts by weight of a hydrogenated terpene resin (Clearon P-105 manufactured by Yashara Chemical Co., Ltd.) was mixed, 10 parts by weight of l-menthol and 10 parts by weight of methyl salicylate were added,
Temperature of 150 ° C from T-die, 50μm thick on release paper
And extruded to form an adhesive layer. This was adhered to the support prepared earlier to prepare a transdermal drug.

Example 2 A polyester (A) solution and a polyester (B) solution were mixed at a weight ratio of 60:40, and dried and coated so as to have a thickness of 20 μm, as in Example 1. To prepare a transdermal drug.

Example 3 Same as Example 1 except that the polyester (A) solution and the polyester (B) solution were mixed at a weight ratio of 80:20, and dried and coated to a thickness of 8 μm. To prepare a transdermal drug.

Example 4 Same as Example 1 except that the polyester (A) solution and the polyester (B) solution were mixed at a weight ratio of 50:50, and dried to be applied to a thickness of 25 μm. To prepare a transdermal drug.

Example 5 The same as Example 1 except that the polyester (A) solution and the polyester (B) solution were mixed at a weight ratio of 10:90, and dried and coated so as to have a thickness of 4 μm. To prepare a transdermal drug.

Example 6 A polyester (A) solution and a polyester (B) solution were mixed at a weight ratio of 60:40, and coronate L (solid content: 75% by weight) which was an ethyl acetate solution of an adduct of trimethylpropanol and tritoluene diisocyanate was added. (100% by weight of polyester) is mixed with 2 parts by weight (since the solid content of polyester is 30% by weight, the solid content weight ratio of polyester / isocyanate (hereinafter simply referred to as “solid content weight ratio”) is 100/5. .). After drying it, thickness 10
A transdermal drug was prepared in the same manner as in Example 1, except that the composition was coated to a thickness of μm and further heated at 60 ° C. for 3 days to crosslink.

Example 7 The polyester (A) solution and the polyester (B) solution were mixed at a weight ratio of 70:30, and 1 part by weight of Coronate L was mixed with 100 parts by weight of the polyester solution (100 parts by weight of solid content). /2.5) Except for this, a transdermal drug was prepared in the same manner as in Example 6.

Example 8 A polyester (A) solution and a polyester (B) solution were mixed at a weight ratio of 50:50, and 3 parts by weight of Coronate L was mixed with 100 parts by weight of the polyester solution (solids weight ratio of 100). /7.5) Except for that, a transdermal drug was prepared in the same manner as in Example 6.

Comparative Example 1 A transdermal drug was prepared in the same manner as in Example 5 except that only the polyester (A) solution was used. Comparative Example 2 A transdermal drug was prepared in the same manner as in Example 2 except that the polyester (A) solution and the polyester (B) solution were mixed at a weight ratio of 40:60.

Comparative Example 3 Ethylene glycol and terephthalic acid were used in a molar ratio of 50:50.
(Lumirror manufactured by Toray Industries, Inc .; hereinafter also referred to as "polyester (C)"), extruded and molded to a thickness of 5 μm.
After drying the polyurethane-based adhesive on a film of
A transdermal drug was prepared in the same manner as in Example 1, except that the composition was coated to a thickness of μm and immediately after drying, was laminated with a soft PVC film to form a support.

Comparative Example 4 A polyester (A) solution and a polyester (B) solution were mixed at a weight ratio of 20:80, dried, and coated so as to have a thickness of 2 μm, in the same manner as in Example 1. Transdermal drugs were prepared. Comparative Example 5 Transdermal administration was performed in the same manner as in Example 1 except that the polyester (A) solution and the polyester (B) solution were mixed at a weight ratio of 20:80, and dried and then coated so as to have a thickness of 30 μm. Created medicine.

Comparative Example 6 A transdermal drug was prepared using only the soft PVC film as it was. Comparative Example 7 The polyester (A) solution and the polyester (B) solution were mixed at a weight ratio of 70:30, and 5 parts by weight of Coronate L was mixed with 100 parts by weight of the polyester solution (solids weight ratio: 100/12. 5) Except for this, a transdermal drug was prepared in the same manner as in Example 6.

Comparative Example 8 The polyester (A) solution and the polyester (B) solution were mixed at a weight ratio of 60:40, and 5 parts by weight of Coronate L was mixed with 100 parts by weight of the polyester solution (solids weight ratio of 100 parts). /12.5), and a transdermal drug was prepared in the same manner as in Example 6, except that coating was performed so that the thickness after drying was 15 μm. Comparative Example 9 The polyester (A) solution and the polyester (B) solution were mixed at a weight ratio of 50:50, and 5 parts by weight of Coronate L was mixed with 100 parts by weight of the polyester solution (solids weight ratio: 100/12. 5) A transdermal drug was prepared in the same manner as in Example 6, except that the composition was dried so as to have a thickness of 20 μm.

Evaluation Method The transdermal drugs obtained in the above Examples and Comparative Examples were evaluated by the following methods, and the results are summarized in Tables 1 and 2. (1) Amount of drug remaining 10 days after the preparation of the drug for transdermal administration, the adhesive layer was taken from the support, l-menthol and methyl salicylate in the adhesive were quantified, and the amount in the adhesive before the preparation of the drug for transdermal administration was determined. As compared with, the remaining ratio is shown in percentage. (2) 10% Modulus A 10% modulus was measured according to JIS K 6732 (the unit is N), and the flexibility was evaluated.

[0033]

[Table 1]

[0034]

[Table 2]

[0035]

EFFECTS OF THE INVENTION The drug support for transdermal administration according to the present invention is flexible and has good followability to the skin, and has a property of preventing drug transfer, so that the amount of drug in the adhesive does not decrease during storage and can be used. Sometimes the required amount of drug can be ensured in the adhesive.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-4-77419 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 47/34 A61K 9/70

Claims (2)

(57) [Claims] 1. A polyvinyl chloride type, a polyvinyl acetate type,
On a 50-180 μm thick film made of polyurethane or polyolefin plastic, 60/4
An ethylene glycol / neopentyl glycol mixed diol mixed in a molar ratio of 0/40/60;
Polyester (A) obtained from terephthalic acid / isophthalic acid mixed dicarboxylic acid mixed at a molar ratio of ４０40/60, the mixed diol, and 90/10 to 70/3
A polyester obtained by mixing a terephthalic acid / sebacic acid mixed dicarboxylic acid mixed at a molar ratio of 0 and a polyester (B) obtained at a weight ratio of (A) / (B) = 50/50 to 90/10 has a thickness of 3 A medicinal support for transdermal administration, wherein the support is laminated to a thickness of up to 28 μm. 2. The medicinal support for transdermal administration according to claim 1, wherein the isocyanate crosslinking agent is contained in an amount of 0 to 10 parts by weight based on 100 parts by weight of the mixed polyester.