KR102436756B1 - A transdermal drug delivery system containing a non-steroidal anti-inflammatory analgesic and salicylic acid derivatives - Google Patents

Abstract

Disclosed is a transdermally absorbed formulation comprising a nonsteroidal anti-inflammatory analgesic.

Description

A transdermal drug delivery system containing a non-steroidal anti-inflammatory analgesic and salicylic acid derivatives

The present invention relates to a transdermal preparation comprising a nonsteroidal anti-inflammatory analgesic (NSAID) having anti-inflammatory and analgesic action or a pharmaceutically acceptable salt thereof as a main ingredient, and a salicylic acid derivative as a transdermal absorption enhancer. The transdermally absorbable preparation according to the present invention stably exists without the drug forming crystals in the adhesive matrix, and can effectively deliver an effective amount of the drug into the body through the skin.

Transdermally absorbed formulations are formulations that can be administered locally or systemically through the skin. Compared with formulations of other routes of administration, including oral administration, transdermal absorption formulations are convenient to administer, avoid the liver first-pass effect, continuous administration for a long time, and easy interruption of absorption if necessary. It is a formulation with advantages in terms of aspects.

For transdermally absorbable formulations that deliver the active ingredient through the skin, it is important to design the formulation so that the active ingredient penetrates the skin well. Since the skin acts as a barrier to prevent the intrusion of foreign substances from the outside or the evaporation of moisture from the body, the permeability of the material is lower than that of a general biological membrane. Therefore, how to improve skin permeability becomes a very important technical task in designing a transdermally absorbable formulation.

In the preparation of transdermal absorption agents, esters of fatty acids and alcohols, alkylmethyl sulfoxides, pyrrolidone compounds, and the like have been mainly used as transdermal absorption enhancers. Since these substances increase the skin permeability in a way that impairs the barrier function of the stratum corneum of the skin, the amount of use must be determined while carefully considering whether side effects such as skin irritation occur. Therefore, there is still a need to select a preferred transdermal absorption enhancer that can minimize the risk of side effects while increasing skin permeability to a satisfactory level.

Korean Patent Publication No. 2003-0000344

Transdermally absorbed formulations containing non-steroidal anti-inflammatory drugs as an active ingredient are widely used in terms of convenience of administration and prevention of side effects. A transdermally absorbable formulation that delivers an active ingredient through the skin requires a skin absorption enhancement technology that can overcome the barrier function of the stratum corneum, the outermost layer of the skin, in order to deliver a sufficient amount of the active ingredient through the skin.

Transdermal absorption enhancers, which are essential for transdermal absorption formulations, increase the skin permeability of active ingredients, but there is a problem in that they may cause side effects depending on the type and amount of the transdermal absorption enhancers and may cause risks to patients.

Therefore, when preparing a transdermal absorption preparation, selection of the transdermal absorption enhancer or appropriate selection of the amount used is of utmost importance.

In the present invention, by blending a salicylic acid derivative as a transdermal absorption enhancer in a transdermal absorption preparation containing a nonsteroidal anti-inflammatory analgesic as an active ingredient, the safety and stability are excellent, and the skin permeability of the active ingredient can be improved.

The transdermally absorbable preparation containing a nonsteroidal anti-inflammatory analgesic according to the present invention has excellent safety and stability, has improved skin permeability of active ingredients, and is easy to manufacture. In addition, when the transdermally absorbable preparation according to the present invention is used, pain can be quickly relieved at the initial stage, and the analgesic effect can be sustained for a long time.

1 is a cross-sectional view of a transdermally absorbed formulation according to the present invention, wherein A is a support layer, B is a drug-containing adhesive layer, and C is a release layer.
2 and 3 are graphs showing the amount of transdermal absorption of Examples and Comparative Examples of the present invention.

The present invention relates to a transdermally absorbed preparation comprising a nonsteroidal anti-inflammatory analgesic and a salicylic acid derivative.

Specifically, the present invention provides a non-steroidal anti-inflammatory analgesic or a pharmaceutically acceptable salt thereof as an active ingredient; and a transdermal absorption agent comprising a salicylic acid derivative as a transdermal absorption enhancer. The transdermally absorbable preparation of the present invention may include a drug-containing adhesive layer, wherein the drug-containing adhesive layer includes a nonsteroidal anti-inflammatory drug or a pharmaceutically acceptable salt thereof, a salicylic acid derivative, and a polymer-based adhesive. .

In addition, the present invention provides (A) a drug-containing adhesive layer comprising a non-steroidal anti-inflammatory drug or a pharmaceutically acceptable salt thereof as an active ingredient, a salicylic acid derivative as a transdermal absorption enhancer, and a polymer-based adhesive; (B) a support layer; And (C) relates to a transdermally absorbable formulation comprising a release layer.

The transdermal preparation according to the present invention is a combination of a nonsteroidal anti-inflammatory analgesic and a salicylic acid derivative as a transdermal absorption enhancer. Therefore, the transdermally absorbable preparation of the present invention may contain other dissolution aids (eg, dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, etc.) that are harmful to the human body or cause side effects due to skin irritation. Even without additionally containing other transdermal absorption enhancers, the transdermal permeability is improved. The transdermally absorbable preparation according to the present invention has increased anti-inflammatory and pain relief effects.

In the present invention, as the polymer-based adhesive, any pressure-sensitive adhesive may be used without limitation, and an acrylic adhesive, an adhesive made of a hydrophobic polymer, or a rubber-based adhesive may be used. Considering the solubility or adhesive strength of the drug, it is preferable to use an acrylic adhesive as the polymer base.

The acrylic pressure-sensitive adhesive that can be used in the present invention is an acrylic high-molecular pressure-sensitive adhesive comprising acrylate or a copolymer of vinyl acetate and acrylate (i) having no functional group, (ii) having a hydroxyl (-OH) group as a functional group. One or two or more selected from the group consisting of (iii) having a carboxyl (-COOH) group as a functional group, and (iv) having both a hydroxyl group and a carboxyl group as a functional group may be used. Preferably, an acrylic pressure-sensitive adhesive having a carboxyl group (-COOH) or simultaneously containing a carboxyl group and a hydroxyl group (-OH) may be used.

In addition, the polymer adhesive agent that can be used in the present invention may be an adhesive agent having a hydrophobic polymer as a main agent. Examples of the hydrophobic polymer include polyisoprene, polyisobutylene, polybutadiene, polystyrene butadiene copolymer, polystyrene isoprene copolymer, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, butyl rubber, natural rubber, One or two or more selected from the group consisting of ethylene vinyl acetate copolymer, polysiloxane and methacrylic acid-based polymer may be used.

The hydrophobic polymer adhesive may further include a tackifying resin and a plasticizer, based on the total weight of the polymer adhesive, the hydrophobic polymer is 20 to 60 wt %, the tackifying resin is 20 to 60 wt %, and the plasticizer is 2 to It may be included in 60% by weight.

The rubber-based polymer adhesive that can be used in the present invention may be one or two or more selected from the group consisting of natural rubber, styrene copolymer, polyisoprene, and polybutadiene.

In the present invention, in addition to the salicylic acid derivative, a transdermal absorption enhancer (eg, fatty acid esters, nonionic surfactants, pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid ethers, etc.) may be further included. However, the transdermal absorption preparation of the present invention can improve the transdermal permeability even if it does not further include other transdermal absorption enhancers.

In the present invention, as the salicylic acid derivative, one or two or more selected from the group consisting of sodium salicylate, methyl salicylate, ethyl salicylate, phenyl salicylate, acetylsalicylic acid, choline salicylate, salicylic acid, glycol salicylate, and the like may be used. .

The transdermal absorption enhancer of the present invention may be used in an amount of 1 to 30% by weight, preferably 1 to 15% by weight, based on the total weight of the drug-containing adhesive layer. If the transdermal absorption enhancer exceeds 30% by weight, the transdermal absorption of the drug is not improved any more, and the physical strength of the transdermal absorption enhancer may be reduced, and in some cases, skin irritation may be caused to the user.

The present invention may further include an antioxidant in order to suppress the decomposition and denaturation of components in the transdermally absorbed formulation.

Antioxidants include Butyl hydroxy toluene, Butyl hydroxy anisole, Propyl gallate, Ascorbic acid, Tocopherol, Tocopherol acetate acetate), one or two or more selected from the group consisting of ascorbyl palmitate may be used. Preferably, butylhydroxytoluene, tocopherol, tocopherol acetate, or butylhydroxyanisole is used.

The antioxidant may be included in the drug-containing adhesive layer in an amount of 0.1 to 5% by weight, preferably 0.1 to 1% by weight, based on the total weight of the drug-containing adhesive layer. When the antioxidant is used in excess of 5% by weight, the antioxidant effect is no longer improved.

In the drug-containing adhesive layer of the transdermal absorption preparation of the present invention, the active ingredient, a nonsteroidal anti-inflammatory drug or a pharmaceutically acceptable salt thereof, is 0.1 to 40% by weight, preferably 1 to 20% by weight, based on the total weight of the drug-containing adhesive layer. It may be included in weight %.

In the present invention, the weight ratio of the percutaneous absorption enhancer to the active material may be in the range of 500:1 to 0.1:1.

In the present invention, the support layer is used to prevent drug loss from the formulation during storage and distribution of the transdermally absorbed formulation or while being attached to the skin, and is thin, flexible, and non-irritating to the skin. As the support layer, for example, a material such as polyethylene terephthalate (PET), polyethylene (PE), polypropylene (PP), ethylene vinyl acetate copolymer (EVA), nylon (Nylon), etc. may be used, and a film of these materials may be used alone, or a laminated film in which two or more films are combined may be used. In addition, when using a film in which two or more films are laminated, an aluminum deposition film may be used for light blocking and moisture proofing.

In the present invention, the release layer is not particularly limited as long as it protects the drug-containing product while the transdermally absorbable preparation is packaged as a product, stored or distributed, and provides convenience so that it can be easily removed when using the product. As the release layer, for example, a film made from polyester, polyvinyl chloride, polyvinylidene chloride, polyethylene terephthalate, polyethylene, ethylene vinyl acetate, etc. can The release layer is coated with a silicone resin or a fluororesin on the surface to which the adhesive layer contacts, and it is preferable to use a polyethylene terephthalate film having excellent long-term stability of the drug.

[Example]

Hereinafter, the present invention will be described in detail in Examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following examples.

One. Example 1-4 and comparative example Manufacturing of 1-3

A nonsteroidal anti-inflammatory drug, a transdermal absorption enhancer, and an adhesive were added to a 70 mL vial in amounts corresponding to Table 1 and mixed for 2 hours. After leaving for 30 minutes to remove air bubbles, a silicone-treated polyethylene terephthalate release film was placed on the coating machine, and the mixed adhesive was dried and then coated to a thickness of 70 μm. Thereafter, after drying in an oven at 80° C. for 3 minutes, the support layer film was laminated and compressed using a compression roller, and then a transdermally absorbable formulation having an area of 70 cm 2 was prepared using a cutter.

The blending amount and transdermal absorption test results of each Example and Comparative Example are shown in Table 1 and FIG. 2 below.

division weight% Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Comparative Example 3 Flurbiprofen 4 4 4 Ketoprofen 4 4 diclofenac 4 4 adhesive -COOH acrylic adhesive 86 86 86 86 96 96 96 percutaneous absorption
enhancer methyl salicylate 10 10 10 glycol salicylate 10

percutaneous absorption Experiment

An isotonic phosphate buffer (Phosphate buffered saline solution, PBS solution pH=7.4) is put as a receptor in a Franz-type diffusion cell, and the temperature is maintained at 32°C similar to that of the skin, and agitation at 600rpm with a magnetic stirrer Dissolved gas in the solution was removed by stirring at a constant speed. Thereafter, a patch cut to fit the upper donor cell of the Franz-type diffusion mechanism was attached to a membrane for transdermal absorption (Strat-M, Merck KGaA, Darmstadt, Germany), and mounted on the Franz-type diffusion mechanism. After that, 200 μl of the receptor part solution was collected every predetermined time, and 200 μl of a new isotonic phosphate buffer (PBS solution pH=7.4) was supplemented. The collected samples were analyzed by high performance liquid chromatography (HPLC), and the analysis conditions were as follows.

Analysis conditions

Column: C18, 4.6mm ×250mm, 5㎛ (Themo hypersil gold)

Mobile phase: Methanol:Water:AA = 55:44:1 (V/V/V)

Flow rate: 1mL/min

Column temperature: 35℃

Injection volume: 20 μl

Detection: UV 254nm

As a result of the experiment, as shown in FIG. 2 , it can be seen that the amount of transdermal absorption of Examples 1 to 4 was much higher than that of Comparative Examples 1 to 3.

One. Example 5 and comparative example 4-6

A nonsteroidal anti-inflammatory analgesic, a transdermal absorption enhancer, and an adhesive were added to a 70 mL vial in amounts corresponding to Table 2 and mixed for 2 hours. After leaving for 30 minutes to remove air bubbles, a silicone-treated polyethylene terephthalate release film was placed on the coating machine, and the mixed adhesive was dried and then coated to a thickness of 70 μm. Thereafter, after drying in an oven at 80° C. for 3 minutes, the support layer film was laminated and compressed using a pressing roller, and then a transdermally absorbable preparation having an area of 70 cm 2 was prepared using a cutter.

The blending amount and transdermal absorption test results of each Example and Comparative Example are shown in Table 2 and FIG. 3 below.

division weight% Example 5 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Flurbiprofen 4 4 4 4 4 adhesive -COOH acrylic adhesive 91 96 91 91 91 percutaneous absorption
enhancer methyl salicylate 5 SMO 5 PGML 5 Oleic acid 5

SMO: sorbitan monooleate

PGML: propylene glycol monolaurate

percutaneous absorption Experiment

An isotonic phosphate buffer (Phosphate buffered saline solution, PBS solution pH=7.4) is put as a receptor in a Franz-type diffusion cell, and the temperature is maintained at 32°C similar to that of the skin, and agitation at 600rpm with a magnetic stirrer Dissolved gas in the solution was removed by stirring at a constant speed. Thereafter, a patch cut to fit the upper donor cell of the Franz-type diffusion mechanism was attached to a membrane for transdermal absorption (Strat-M, Merck KGaA, Darmstadt, Germany), and mounted on the Franz-type diffusion mechanism. After that, 200 μl of the receptor part solution was collected every predetermined time, and 200 μl of a fresh isotonic phosphate buffer (PBS solution pH=7.4) was supplemented. The collected samples were analyzed by high performance liquid chromatography (HPLC), and the analysis conditions were as follows.

Analysis conditions

Column: C18, 4.6mm ×250mm, 5㎛ (Themo hypersil gold)

Mobile phase: Methanol:Water:AA = 55:44:1 (V/V/V)

Flow rate: 1mL/min

Column temperature: 35℃

Injection volume: 20 μl

Detection: UV 254nm

As a result of the experiment, as shown in FIG. 3 , it can be seen that the amount of percutaneous absorption of Example 5 is very superior to that of Comparative Examples 4-7.

The transdermally absorbable preparation according to the present invention has excellent transdermal absorption ability, high stability, simple storage and use, and easy manufacture.

Claims (7)

Any one nonsteroidal anti-inflammatory analgesic selected from the group consisting of flurbiprofen, ketoprofen and diclofenac as an active ingredient; and a salicylic acid derivative of either methyl salicylate or glycol salicylate as a transdermal absorption enhancer, comprising:
The transdermally absorbable formulation includes a drug-containing adhesive layer, wherein the drug-containing adhesive layer includes the nonsteroidal anti-inflammatory drug, the salicylic acid derivative, and a polymer-based adhesive,
The polymer-based adhesive is an acrylic adhesive having a carboxyl group (-COOH),
The transdermally absorbable preparation is in the form of a patch, cataplasma, or patch. delete delete According to claim 1, wherein the non-steroidal anti-inflammatory analgesic agent is contained in an amount of 0.1 to 40% by weight based on the total weight of the drug-containing adhesive layer, and the transdermal absorption enhancer is based on the total weight of the drug-containing adhesive layer. Transdermal absorption formulation, characterized in that it is contained in an amount of 1 to 30% by weight. delete The transdermal absorption preparation according to claim 1, further comprising an antioxidant. delete

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