KR20130049353A - Transdermal patch for administering fentanyl - Google Patents

Abstract

The present invention relates to a transdermal patch system containing fentanyl as an active ingredient, wherein the fentanyl-containing low-cost adhesive drug storage layer has no functional group or a polyacrylate pressure-sensitive adhesive having a hydroxy functional group; And it provides a transdermal patch system containing fentanyl containing 20 to 40% by weight of a mixture of a polyacrylate-based pressure-sensitive adhesive having a carboxyl group and a polydimethylsiloxane pressure-sensitive adhesive as a pressure-sensitive adhesive for fentanyl release control pressure-sensitive adhesive. The transdermal patch system containing the fentanyl of the present invention, while the production process is simple, has excellent skin permeability and long-term sustainability of the drug, and does not use additives and skin permeation accelerators, so that the skin irritation is significantly low when used for a long time. Even without fentanyl can be safely delivered to the body without any side effects, the manufacturing method is very simple and economically very useful. Therefore, the transdermal patch system containing the fentanyl of the present invention can produce a patch system capable of drug release for a long time, and is excellent in compliance and usability of the patient.

Description

Transdermal patch for administering fentanyl

The present invention relates to a transdermal patch system containing fentanyl as an active ingredient.

Fentanyl (fentanyl, N-phenyl-N- [1- (2-phenylethyl) -4-piperidinyl] propana mide) is a synthetic drug that shows 50-100 times stronger anesthetic and analgesic effects than morphine. It is used to relieve pain of patients after surgery.

However, fentanyl has shortcomings because of its short half-life. The maximum analgesic effect after intramuscular administration of fentanyl occurs within 1 hour and is known to be shorter in duration than morphine.

Therefore, the use of fentanyl injectables puts a burden on the patient because they need to be administered at frequent intervals for continuous analgesic effects. Administration of fentanyl in large amounts can also increase the induction of tolerance and body dependence to fentanyl.

In order to solve the above problems, research has been conducted on the percutaneous administration of fentanyl, which can maintain a constant blood concentration and reduce side effects compared to the injection.

Known techniques related to the previously known transdermal formulation of fentanyl are as follows.

WO 89/10108 and Korean Patent No. 1995-0001968 disclose laminated composites for transdermal administration of fentanyl consisting of a support layer, fentanyl, PGML and an amine pressure-sensitive adhesive polymer. The hybrids can be rapidly transdermally administered fentanyl within 1 day of use due to the use of a low-solubility pressure-sensitive adhesive for fentanyl, but do not exhibit long-term analgesic effects, causing frequent frequency of administration.

U.S. Patent No. 4588580 discloses a system for fentanyl administration in connection with already commercially available storage solid fentanyl transdermal absorption agents. The fentanyl transdermal absorption device shown in the patent is composed of a support layer, a storage layer of a gel containing ethanol as a drug and a skin permeation accelerator, a release rate control membrane layer, an adhesive layer and a release layer, so that the release rate of the drug can be easily controlled and the skin permeation is performed. Although it has the advantage of promoting, due to the stimulation caused by ethanol used as a skin permeation accelerator may cause side effects such as skin irritation when used for a long period of about 3 days. The formulation also consists of several layers, requiring a fairly complex manufacturing process.

Korean Patent Laid-Open Publication No. 1999-0028787 discloses a fentanyl-containing transdermal administration tape formulation consisting of fentanyl or a salt thereof, an adhesive and sodium acetate. The formulation has a very good skin permeability, low skin irritation and stability over time by adding sodium acetate to the pressure-sensitive adhesive, while polyisobutylene and styrene-isoprene-styrene block airborne rubber pressure-sensitive adhesives having low moisture and air permeability. When applied to the skin for a long time using the coalescence can be easily peeled off from the skin by sweat, the manufacturing method is also complicated.

U.S. Patent No. 4906463 discloses a pharmaceutical composition for transdermal / transmucosal administration consisting of a skin permeation accelerator such as fentanyl, fatty acids, and a water-insoluble polymer mixture. The composition has excellent drug release and elasticity to improve adhesion to the skin, but the problem of skin irritation due to the skin permeation accelerator still remains.

Korean Patent Laid-Open Nos. 2001-0036685 and 2002-0038808 are fentanyl matrix transdermal dosing agents, and are characterized in that a matrix layer made of a tacky polymer having different solubility of fentanyl is adjacent to each other. The formulation can be released early in the administration of a certain amount of fentanyl from the adhesive polymer with low solubility in fentanyl to reduce the time to reach the effective blood concentration in the body, and can accelerate the onset of the analgesic effect, after a certain time the high solubility of fentanyl The drug is released from the adhesive polymer to maintain the effective blood concentration, thereby maintaining a long-term analgesic effect. Since the agent releases fentanyl from different matrix layers at the beginning and the end of administration, it is possible to speed up the onset of analgesic effect and maintain the analgesic effect for a long time.

However, in order to prepare the formulation, two drug-containing adhesive solutions are prepared separately, one drug-containing adhesive solution is applied on a support layer, and the other drug-containing adhesive solution is applied and dried on a release layer. The layers must face each other and must be precisely laminated so that they do not overlap and adjoin each other. Subsequently, the adjacent drug-containing adhesive layers may be precisely cut to have a constant area ratio, so that the preparation of the preparation may be complicated, and the loss rate of fentanyl generated in the process may be increased.

Korean Patent Laid-Open Publication No. 2003-0021418 discloses a matrix transdermal administration agent of fentanyl, but this also adds a low boiling point permeation accelerator to the matrix layer, which may increase skin irritation.

The problem to be solved by the present invention is to provide a patch system that can be controlled at a skin penetration rate equivalent to that of a conventional fentanyl patch system without containing a skin permeation accelerator.

According to an aspect of the present invention,

In the transdermal patch system containing a fentanyl consisting of a drug protective layer, a self-adhesive drug storage layer containing fentanyl and a release layer,

The self-adhesive drug storage layer

60 to 80% by weight of a polyacrylate-based pressure sensitive adhesive having no functional group or having a hydroxy functional group; And

20 to 40% by weight of a mixture of a polyacrylate-based pressure-sensitive adhesive having a carboxyl group and a polydimethylsiloxane pressure-sensitive adhesive as a pressure-sensitive adhesive for fentanyl release control

It provides a transdermal patch system containing fentanyl, characterized in that it comprises a.

In the fentanyl-containing transdermal patch system according to the present invention as described above, the mixing ratio of the mixture of the polyacrylate-based pressure-sensitive adhesive and polydimethylsiloxane pressure-sensitive adhesive having a carboxyl functional group as the pressure-sensitive adhesive for fentanyl release is 1: 5 to It is preferable that it is 5: 1.

The transdermal patch system containing the fentanyl of the present invention, while the production process is simple, has excellent skin permeability and long-term sustainability of the drug, and does not use additives and skin permeation accelerators, so the skin irritation is remarkably low. Fentanyl can be safely delivered to the body without side effects, and the manufacturing method is also very simple and economically very useful. Therefore, the transdermal patch system containing the fentanyl of the present invention is very excellent in compliance and usability of the patient.

1 illustrates a transdermal patch system containing fentanyl according to the invention.
2 to 3 is a graph showing the results of the drug release rate evaluation (skin permeation test) for the Examples and Comparative Examples according to the present invention.

Hereinafter, the present invention will be described in detail.

The transdermal patch system containing fentanyl according to the present invention comprises a drug protective layer (A), a self-adhesive drug storage layer (B) and a release layer (C) containing fentanyl.

In the transdermal patch system containing fentanyl according to the present invention, the fentanyl content and the release layer (C) of the self-adhesive drug storage layer (B) containing the drug protective layer (A) and fentanyl are the present invention. As is well known in the art, it can be used as it is, the drug protection layer is thin and flexible to prevent the loss of the drug from the formulation during adhesion or storage on the skin, it is not reactive with the skin Use ones that do not cause allergic reactions.

Water absorption to prevent the patch system from falling off by monolayer films such as polyester, polyurethane, polyethylene, polypropylene, polyolefin, polyethylene terephthalate, aluminum treated polyester, or moisture emitted from the human body as a drug protection layer Nonwoven fabrics, cotton fabrics, fabrics and the like, and a multilayer laminate film in which the single layer film is laminated may be used, and any of the drug-protective films used in the conventional patch system may be used.

In addition, the release layer serves to support the product when the patch system is cut to an appropriate size, and is removed when the product is applied to the skin, and is used in aluminum, cellulose, polyester, polyethylene, and polypropylene. Such a film or a thin film made of paper can be used, and these films can be laminated as necessary. In addition, it is preferable to use a peeling layer that removes the debris of the matrix and easily removes the peeling layer from the patch system, and may be any material or form commonly used in transdermal formulations. .

In addition, the content of fentanyl contained in the self-adhesive drug storage layer may be applied as it is applied to the transdermal patch system, which is attached once and used continuously for 3 days.

The present invention is a low-pressure adhesive pressure-sensitive adhesive of the fentanyl-containing transdermal patch system while studying a patch system capable of sufficiently exhibiting medicinal effects for a long time without skin irritation, does not have a functional group or a hydroxy functional group Based on the fact that fentanyl has a very high skin permeability when using an acrylate polymer, and a acrylate polymer having no functional group or a hydroxy functional group as a pressure-sensitive adhesive is basically used to control drug release. As the pressure-sensitive adhesive for fentanyl, it is difficult for fentanyl to escape from the polymer matrix, and the skin permeability of the acrylate-based polymer having a carboxyl group and the acrylate-based polymer having a carboxyl group are greatly reduced. A by containing the polydimethylsiloxane pressure sensitive adhesive that can be corrected at an appropriate ratio it will be with the completion of the present invention.

That is, the present invention uses the self-adhesive drug storage layer (B) as a main pressure sensitive adhesive, which is a acrylate-based polymer pressure sensitive adhesive containing no functional group or having a hydroxy functional group, and controlling the release of the drug therein for 3 days. In order to produce a continuous effect during the release control pressure-sensitive adhesive is composed of a mixture of an acrylate-based polymer pressure-sensitive adhesive having a carboxyl functional group and a polymethylsiloxane pressure-sensitive adhesive as a core for the release control pressure-sensitive adhesive.

The acrylate-based polymer pressure-sensitive adhesive having no functional group usable in the present invention, the acrylate-based polymer pressure-sensitive adhesive having a hydroxy functional group and the acrylate-based polymer pressure-sensitive adhesive having a carboxyl functional group are specially known in the art. Can be used without limitation.

For example, the acrylate polymer pressure sensitive adhesive having no functional group or the acrylate polymer pressure sensitive adhesive having a hydroxy functional group is 50 to 90% by weight of an alkyl methacrylate having 4 to 17 carbon atoms, which is self-adhesive. Polyacrylate-based reduced pressure containing 50% by weight or less of methyl acrylate or vinyl acetate and no functional groups or 2-hydroxyethyl acrylate or 2-hydroxyethyl methacrylate containing 20% by weight or less of functional groups Adhesives can be used. Suitable polyacrylate pressure sensitive adhesives are commercially available and are available from Henkel, DuroTak 87-4098, DuroTak 87-9085, DuroTak 87-9088, DuroTak 87-9301, DuroTak Elite 87-900A, DuroTak Elite 87 Pressure sensitive adhesives sold as -901A, DuroTak # 87-2287, DuroTak # 87-4287, DuroTak # 87-2510, DuroTak # 87-2525, and DuroTak # 87-2516.

In addition, examples of the carboxyl group-containing acrylate pressure-sensitive adhesive used to control drug release include polyacrylate-based pressure-sensitive adhesives in which the functional group-containing monomer is acrylic acid or methacrylic acid, specifically, carboxyl group functional groups (acrylic acid, methacrylic). And polyacrylate pressure-sensitive adhesives containing 20% by weight or less of acid). Suitable polyacrylate pressure sensitive adhesives are commercially available and are available from Henkel, DuroTak 87-200A, DuroTak 87-202A, DuroTak 87-2353, DuroTak 87-2852, DuroTak 87-2051, DuroTak 87- 2052, pressure sensitive adhesive sold as DuroTak 87-2054.

In addition, polydimethylsiloxane pressure-sensitive adhesives used for controlling drug release together with acrylate-based polymer pressure-sensitive adhesives having a carboxyl functional group may also be used without particular limitation as long as they are well known in the art to which the present invention pertains. It is prepared by the condensation reaction of polysilicate resin and polydimethylsiloxane having a knol group, it is possible to control the properties of the silicone pressure-sensitive adhesive according to their ratio. Suitable silicone pressure sensitive adhesives are commercially available and are marketed by Dow Corning Corporation (medical products) under the trade names BIO-PSA 7-4102, BIO-PSA 7-4202, BIO-PSA 7-4302, BIO-PSA 7 -4101, BIO-PSA 7-4201, BIO-PSA 7-4301, BIO-PSA 7-4401, BIO-PSA 7-4501, BIO-PSA 7-4601, BIO-PSA 7-4402, BIO-PSA 7- 4502, silicone pressure sensitive adhesive sold as BIO-PSA 7-4602.

The mixture of the above-mentioned drug release control pressure sensitive adhesive should not exceed 40% by weight in the drug storage layer. If it exceeds 40% by weight, the saturated solubility is increased, so that it is difficult to release the active substance for a long time, and it is difficult to maintain a desired release rate. Preferably it is contained 20 to 40% by weight.

In addition, according to the weight ratio of the polyacrylate pressure-sensitive adhesive and polydimethylsiloxane pressure-sensitive adhesive having a carboxyl functional group in the pressure-sensitive adhesive mixture for drug release control, it is possible to control the release rate of the active material, the weight ratio should be 5: 1 to 1: 5. .

The greater the weight ratio of the polydimethylsiloxane pressure sensitive adhesive, the faster the release rate of the active material. If the weight ratio is greater than 1: 5, it is difficult to secure the solubility of the active substance, and it is difficult to control the release for a long time. If the ratio is lower than 5: 1, the release of the active substance is difficult due to the influence of the saturated solubility of the polyacrylate pressure-sensitive adhesive.

In addition, in adjusting the mixing ratio, the ratio of saturated solubility to fentanyl should be 30: 1 to 20: 1.

1.Polyacrylate pressure-sensitive adhesive containing 20% by weight or less of carboxyl functional group (acrylic acid, methacrylic acid)

2. Suitable polyacrylate pressure sensitive adhesives are commercially available and are available from Henkel, DuroTak 87-200A, DuroTak 87-202A, DuroTak 87-2353, DuroTak 87-2852, DuroTak 87-2051, DuroTak 87- 2052, pressure sensitive adhesive sold as DuroTak 87-2054.

2. Polydimethylsiloxane pressure sensitive adhesive is prepared by the condensation reaction of polysilicate and polydimethylsiloxane having a silanol group, and the physical properties of the silicone pressure sensitive adhesive can be controlled according to their ratio.

3. Suitable silicone pressure sensitive adhesives are commercially available and available from Daw Corning Corporation, medical products under the trade names BIO-PSA 7-4102, BIO-PSA 7-4202, BIO-PSA 7-4302, BIO-PSA. 7-4101, BIO-PSA 7-4201, BIO-PSA 7-4301, BIO-PSA 7-4401, BIO-PSA 7-4501, BIO-PSA 7-4601, BIO-PSA 7-4402, BIO-PSA 7 -4502, silicone pressure sensitive adhesive sold as BIO-PSA 7-4602.

4. The mixture of pressure sensitive adhesive for drug release control should not exceed 40% by weight in the drug storage layer. If it exceeds 40% by weight, the saturated solubility is increased, so that it is difficult to release the active substance for a long time, and it is difficult to maintain a desired release rate.

Hereinafter, the present invention will be described through examples.

≪ Example 1 >

Polyacrylate Pressure Sensitive Adhesive DuroTak  48.6 g of 87-200A (Henkel AG & Co., KGaA, Germany) and 6.48 g of a silicone pressure sensitive adhesive Bio PSA 4202 (Daw corning corporation) were homogeneously mixed. 2.78 g of this mixture and 7.99 g of polyacrylate pressure-sensitive adhesive DuroTak 87-9085 (Henkel AG & Co., KGaA, Germany) were stirred well, and 39 mg of Eudragit EPO (Evonik Rohm GmbH) was dissolved in 1 g of ethyl acetate. Was added to obtain an adhesive solution. After dissolving 344 mg of fentanyl in the adhesive solution, the adhesive solution was applied to a polyethylene terephthalate liner (ScotchpakTM 1022, 3M) so that the coating thickness was 47 um after drying. After drying for 5 minutes at room temperature for about 10 minutes with hot air at 80 ° C., a patch was prepared by lining with Scotchpak ™ 9732 and cutting the fentanyl content to 0.4 mg per unit area.

<Example 2>

Polyacrylate Pressure Sensitive Adhesive DuroTak  53.2 g of 87-200A (Henkel AG & Co., KGaA, Germany) and 19.5 g of silicone pressure sensitive adhesive Bio PSA 4202 (Daw corning corporation) were homogeneously mixed. After stirring 1.18 g of this mixture and 2.74 g of polyacrylate pressure-sensitive adhesive DuroTak 87-9085 (Henkel AG & Co., KGaA, Germany), 28 mg of Eudragit EPO (Evonik Rohm GmbH) was dissolved in 1 g of ethyl acetate. Was added to obtain an adhesive solution. After dissolving 244 mg of fentanyl in the adhesive solution, the adhesive solution was applied to a polyethylene terephthalate liner (ScotchpakTM 1022, 3M) so that the coating thickness was 47 um after drying. After drying for 5 minutes at room temperature for about 10 minutes with hot air at 80 ° C., a patch was prepared by lining with Scotchpak ™ 9732 and cutting the fentanyl content to 0.4 mg per unit area.

<Example 3>

Polyacrylate Pressure Sensitive Adhesive DuroTak  15.6 g of 87-200A (Henkel AG & Co., KGaA, Germany) and 47.9 g of silicone pressure sensitive adhesive Bio PSA 4202 (Daw corning corporation) were homogeneously mixed. After stirring 1.86 g of this mixture and 5.65 g of polyacrylate pressure-sensitive adhesive DuroTak 87-9085 (Henkel AG & Co., KGaA, Germany), 26 mg of Eudragit EPO (Evonik Rohm GmbH) was dissolved in 1 g of ethyl acetate. Was added to obtain an adhesive solution. After dissolving 230 mg of fentanyl in the adhesive solution, the adhesive solution was applied to a polyethylene terephthalate liner (ScotchpakTM 1022, 3M) so that the coating thickness was 47 um after drying. After drying for 5 minutes at room temperature for about 10 minutes with hot air at 80 ° C., a patch was prepared by lining with Scotchpak ™ 9732 and cutting the fentanyl content to 0.4 mg per unit area.

<Example 4>

Polyacrylate Pressure Sensitive Adhesive DuroTak  43.2 g of 87-200A (Henkel AG & Co., KGaA, Germany) and 29.5 g of silicone pressure sensitive adhesive Bio PSA 4202 (Daw corning corporation) were homogeneously mixed. After stirring 3.0 g of this mixture and 3.5 g of polyacrylate pressure-sensitive adhesive DuroTak 87-9085 (Henkel AG & Co., KGaA, Germany), 25 mg of Eudragit EPO (Evonik Rohm GmbH) was dissolved in 1 g of ethyl acetate. Was added to obtain an adhesive solution. After dissolving 218 mg of fentanyl in the adhesive solution, the adhesive solution was applied to a polyethylene terephthalate liner (Scotchpak ™ 1022, 3M) so that the coating thickness was 47 um after drying. After drying for 5 minutes at room temperature for about 10 minutes with hot air at 80 ° C., a patch was prepared by lining with Scotchpak ™ 9732 and cutting the fentanyl content to 0.4 mg per unit area.

&Lt; Comparative Example 1 &

Polyacrylate Pressure Sensitive Adhesive DuroTak  70.0 g of 87-200A (Henkel AG & Co., KGaA, Germany) and 5.0 g of a silicone pressure sensitive adhesive Bio PSA 4202 (Daw corning corporation) were homogeneously mixed. After stirring 1.5 g of this mixture and 4.0 g of polyacrylate pressure-sensitive adhesive DuroTak 87-9085 (Henkel AG & Co., KGaA, Germany), 20 mg of Eudragit EPO (Evonik Rohm GmbH) was dissolved in 2 g of ethyl acetate. Was added to obtain an adhesive solution. After dissolving 170 mg of fentanyl in the adhesive solution, the adhesive solution was applied to a polyethylene terephthalate liner (ScotchpakTM 1022, 3M) so that the coating thickness was 47 um after drying. After drying for 5 minutes at room temperature for about 10 minutes with hot air at 80 ° C., a patch was prepared by lining with Scotchpak ™ 9732 and cutting the fentanyl content to 0.4 mg per unit area.

Comparative Example 2

5.0 g of polyacrylate pressure sensitive adhesive DuroTak® 87-200A (Henkel AG & Co., KGaA, Germany) and 30.0 g of silicone pressure sensitive adhesive Bio PSA 4202 (Daw corning corporation) were homogeneously mixed. After stirring 1.0 g of this mixture and 3.5 g of polyacrylate pressure-sensitive adhesive DuroTak90 87-9085 (Henkel AG & Co., KGaA, Germany), 17 mg of Eudragit EPO (Evonik Rohm GmbH) was dissolved in 1 g of ethyl acetate. Was added to obtain an adhesive solution. After dissolving 151 mg of fentanyl in the adhesive solution, the adhesive solution was applied to a polyethylene terephthalate liner (ScotchpakTM 1022, 3M) so that the coating thickness was 47 um after drying. After drying for 5 minutes at room temperature for about 10 minutes with hot air at 80 ° C., it was lined with Scotchpak ™ 9732 and cut to obtain 0.4 mg of fentanyl per unit area to prepare a patch.

&Lt; Comparative Example 3 &

Polyacrylate Pressure Sensitive Adhesive DuroTak  5.0 g of 87-200A (Henkel AG & Co., KGaA, Germany) and 35.0 g of polyacrylate pressure-sensitive adhesive DuroTak 87-9085 (Henkel AG & Co., KGaA, Germany) were stirred well and 3.5 g of this mixture A pressure-sensitive adhesive solution was obtained by adding a solution of 17 mg of Eudragit EPO (Evonik Rohm GmbH) in 1 g of ethyl acetate. After dissolving 151 mg of fentanyl in the adhesive solution, the adhesive solution was applied to a polyethylene terephthalate liner (ScotchpakTM 1022, 3M) so that the coating thickness was 47 um after drying. After drying for 5 minutes at room temperature for about 10 minutes with hot air at 80 ° C., a patch was prepared by lining with Scotchpak ™ 9732 and cutting the fentanyl content to 0.4 mg per unit area.

<Example 5>

Polyacrylate Pressure Sensitive Adhesive DuroTak  53.2 g of 87-200A (Henkel AG & Co., KGaA, Germany) and 19.5 g of silicone pressure sensitive adhesive Bio PSA 4202 (Daw corning corporation) were homogeneously mixed. After stirring 1.0 g of this mixture and 4.5 g of polyacrylate pressure-sensitive adhesive DuroTak 87-2516 (Henkel AG & Co., KGaA, Germany), 23 mg of Eudragit EPO (Evonik Rohm GmbH) was dissolved in 1 g of ethyl acetate. Was added to obtain an adhesive solution. After dissolving 206 mg of fentanyl in the adhesive solution, the adhesive solution was applied to a polyethylene terephthalate liner (ScotchpakTM 1022, 3M) so that the coating thickness was 47 um after drying. After drying for 5 minutes at room temperature for about 10 minutes with hot air at 80 ° C., a patch was prepared by lining with Scotchpak ™ 9732 and cutting the fentanyl content to 0.4 mg per unit area.

<Example 6>

Polyacrylate Pressure Sensitive Adhesive DuroTak  53.2 g of 87-200A (Henkel AG & Co., KGaA, Germany) and 19.5 g of silicone pressure sensitive adhesive Bio PSA 4202 (Daw corning corporation) were homogeneously mixed. After stirring 2.0 g of this mixture and 5.0 g of polyacrylate pressure-sensitive adhesive DuroTak 87-2516 (Henkel AG & Co., KGaA, Germany), 30 mg of Eudragit EPO (Evonik Rohm GmbH) was dissolved in 1 g of ethyl acetate. Was added to obtain an adhesive solution. After dissolving 261 mg of fentanyl in the adhesive solution, the adhesive solution was applied to a polyethylene terephthalate liner (ScotchpakTM 1022, 3M) so that the coating thickness was 47 um after drying. After drying for 5 minutes at room temperature for about 10 minutes with hot air at 80 ° C., a patch was prepared by lining with Scotchpak ™ 9732 and cutting the fentanyl content to 0.4 mg per unit area.

&Lt; Example 7 >

Polyacrylate Pressure Sensitive Adhesive DuroTak  53.2 g of 87-200A (Henkel AG & Co., KGaA, Germany) and 19.5 g of silicone pressure sensitive adhesive Bio PSA 4202 (Daw corning corporation) were homogeneously mixed. After stirring 2.0 g of this mixture and 3.5 g of polyacrylate pressure-sensitive adhesive DuroTak 87-2516 (Henkel AG & Co., KGaA, Germany), 23 mg of Eudragit EPO (Evonik Rohm GmbH) was dissolved in 1 g of ethyl acetate. Was added to obtain an adhesive solution. After dissolving 207 mg of fentanyl in the adhesive solution, the adhesive solution was applied to a polyethylene terephthalate liner (ScotchpakTM 1022, 3M) so that the coating thickness was 47 um after drying. After drying for 5 minutes at room temperature for about 10 minutes with hot air at 80 ° C., a patch was prepared by lining with Scotchpak ™ 9732 and cutting the fentanyl content to 0.4 mg per unit area.

&Lt; Example 8 >

Polyacrylate Pressure Sensitive Adhesive DuroTak  53.2 g of 87-200A (Henkel AG & Co., KGaA, Germany) and 19.5 g of silicone pressure sensitive adhesive Bio PSA 4202 (Daw corning corporation) were homogeneously mixed. After stirring 2.0 g of this mixture and 2.0 g of polyacrylate pressure-sensitive adhesive DuroTak 87-2516 (Henkel AG & Co., KGaA, Germany), 18 mg of Eudragit EPO (Evonik Rohm GmbH) was dissolved in 1 g of ethyl acetate. Was added to obtain an adhesive solution. After dissolving 152 mg of fentanyl in the adhesive solution well, the adhesive solution was applied to a polyethylene terephthalate liner (ScotchpakTM 1022, 3M) so that the coating thickness was 47 um after drying. After drying for 5 minutes at room temperature for about 10 minutes with hot air at 80 ° C., a patch was prepared by lining with Scotchpak ™ 9732 and cutting the fentanyl content to 0.4 mg per unit area.

<Test Example 1: Comparison of skin penetration rates of Examples 1 to 4>

As shown in Table 1, Examples 1 to 3 are dry weight ratios between a mixture of a non-functional group polyacrylate pressure sensitive adhesive and a pressure sensitive adhesive having a carboxyl functional group serving as a release control and a silicone pressure sensitive adhesive. Is 70:30 and Example 4 is 50:50.

In Examples 1 to 3, the dry weight ratios of the controlled release pressure-sensitive adhesive mixture were 5: 1, 4: 2, and 1: 5, respectively, and Example 4 was 5: 1.

Example 1 Example 2 Example 3 Example 4 DuroTak_87-9085 75 75 75 50 DuroTak_87-200A 25 20 25 41.7 BIO_PSA-4202 5 10 5 8.3 Sum 100 100 100 100

Drug release rate evaluation (skin permeation test) was performed for Examples 1 to 4 as follows, and the results are shown in FIG. 2.

The skin permeation test for drug release rate was evaluated using Franz modififed diffusion cell system (Microette Plus, Hanson Research, USA). The receptor layer was 7.5 ml of pH 7.5 isotonic phophate saline, and allowed to diffuse properly, the drug permeated at 300 rpm, and maintained at 37.0 W 0.5 ° C. The skin of the extracted hairless mouse (6 weeks old, male) was hydrated in saline solution for about 30 minutes until room temperature, and then mounted in a cell, and the fentanyl-containing patch prepared on the skin was attached to the skin, followed by experiment. Samples were collected at an appropriate time by 0.5 ml using an autosampler system (Autoplus mulltifil, Hanson Research, USA), and the same amount of receptor fluid was replenished. The concentration of fentanyl in the sample was measured using ultra-fast liquid chromatography (UPLC Waters, USA), and the skin permeation rate (ug / cm2 / hr) was determined at steady-state.

As shown in Figure 2 it can be seen that the release of the active material is controlled according to the dry weight ratio of the mixture of the release control pressure-sensitive adhesive, when Example 1 and Example 4, when the release control mixture is 50%, the mixture As the dry weight ratio of the pressure-sensitive adhesive having a carboxyl functional group contained in it increases, the saturation solubility increases, so that the release rate is slowed.

<Test Example 2: Comparison of skin penetration rates of Examples 5 to 8>

As shown in Table 2, Examples 5 to 8 are drying between a mixture of a hydroxy functional group-containing polyacrylate pressure sensitive adhesive and a pressure sensitive adhesive having a carboxyl functional group serving as a release control and a silicone pressure sensitive adhesive. The weight ratio is 80:20, 70:30, 60; 40, 50:50, respectively, and the composition of the controlled release pressure-sensitive adhesive mixture has a dry weight ratio of the pressure-sensitive adhesive having a carboxyl group and the silicone pressure-sensitive adhesive 2: 1.

Example 5 Example 6 Example 7 Example 8 DuroTak_87-2516 80 70 60 50 DuroTak_87-200A 13.3 20 26.7 33.3 BIO_PSA-4202 6.7 10 13.3 16.7 Sum 100 100 100 100

Drug release rate evaluation (skin permeation test) was performed in the same manner as in Test Example 1 for Examples 5 to 8, and the results are shown in FIG. 3.

As shown in FIG. 3, the higher the dry weight ratio of the carboxyl group is, the lower the release rate and the retention time of the active substance are. In Example 5, the lower the dry weight ratio of the carboxyl group is, the higher the release rate is, the longer the release rate is maintained Able to know.

<Test Example 3: Comparison of skin penetration rate of Comparative Examples 1 to 3>

As shown in Table 3 below, when the dry weight ratio of the polyacrylate and the silicone pressure-sensitive adhesive in the emission control layer is 9: 1, 1: 9, and 10: 0, skin permeability is also compared.

Comparative Example 1 Comparative Example 2 Comparative Example 3 DuroTak_87-9085 70 70 70 DuroTak_87-200A 27 3 30 BIO_PSA-4202 3 27 0 Sum 100 100 100

About the drug release rate evaluation (skin permeation test) about Comparative Examples 1-3, it carried out similarly to the test example 1, and the result is shown in FIG.

As shown in Figure 4, Comparative Example 1 has a lower release rate, because the effect of the polyacrylate on the active material than the effect of the silicone pressure-sensitive adhesive, and in the case of Comparative Example 2, because the weight ratio of the silicone pressure-sensitive adhesive is high, Although the initial release rate is fast, it can be seen that after 24 hours, the rate is significantly decreased.

In Comparative Example 3, in which the silicone pressure-sensitive adhesive was not added, it could be seen that no release was caused by the action between the active material and the polyacrylate.

A: drug protective layer
B: Self-adhesive Drug Storage Layer Containing Fentanyl
C: release layer

Claims (2)

In the transdermal patch system containing a fentanyl consisting of a drug protective layer, a self-adhesive drug storage layer containing fentanyl and a release layer,
The low adhesive drug storage layer is
60 to 80% by weight of a polyacrylate-based pressure sensitive adhesive having no functional group or having a hydroxy functional group; And
20 to 40% by weight of a mixture of a polyacrylate-based pressure-sensitive adhesive having a carboxyl group and a polydimethylsiloxane pressure-sensitive adhesive as a pressure-sensitive adhesive for fentanyl release control
A transdermal patch system containing fentanyl, characterized in that it contains. The method of claim 1,
A fentanyl-containing patch system for transdermal administration, wherein the mixing ratio of the polyacrylate-based pressure-sensitive adhesive having a carboxyl functional group and the polydimethylsiloxane pressure-sensitive adhesive as the fentanyl release control pressure-sensitive adhesive is 1: 5 to 5: 1.

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