KR20100089669A - A transdermal therapeutic system of nicotine and production process therefor - Google Patents

Abstract

PURPOSE: A transdermal therapy system containing nicotine for treating smoking is provided to prevent drug release at once. CONSTITUTION: A nicotine transdermal therapy system comprises a storage layer of monolayer containing 1-30 weight% of nicotine, 0.1-30 weight% of transdermal promoter, 0.01-30 weight% of nicotine volatilization inhibitor; and a support. The nicotine volatilization inhibitor is acetic acid, methasulfonic acid, oxalic acid, phosphoric acid, benzoic acid, or organic acid of 3-8 carbon atoms. The transdermal promoter is fatty acid ether, non-ionic surfactant, isopropyl myristate, tanscutol, triacetin, pyrrolidone derivatives, fatty acid of 2-18 carbon atoms, fatty acid alcohol of 2-18 carbon atoms, and fatty acid ester of 2-18 carbon atoms.

Description

A transdermal therapeutic system of nicotine and production process therefor}

The present invention relates to a nicotine patch containing nicotine, a smoking therapeutic agent, as an active ingredient, and provides a transdermal treatment system having a constant nicotine content and consisting of a single layer, and a method of manufacturing the same.

Nicotine is a drug used as a therapeutic for smoking, and a representative formulation is a patch-type preparation. The amount of active ingredients of commercially available patches are 17.5mg (10cm 2), 35mg (20cm 2), 52.5 (30cm 2) according to the amount of smoking to reduce the amount of nicotine in the human body to help completely quit smoking.

Nicotine is a highly volatile and toxic drug, and volatilization of nicotine increases safety risks and environmental burdens. Accordingly, various methods of preparing nicotine transdermal agents are known in view of such a point. In addition, nicotine is known to be highly permeable to polymers commonly used in transdermal absorbents, so that a system of several layers is required to control skin permeability, thereby increasing manufacturing cost and reducing manufacturing efficiency.

US Patent 6,264,977 B1 describes a new transdermal treatment system with an active ingredient reservoir. The system describes that the manufacturing cost is lower than the existing system and is suitable for compounds which are less volatile and unstable in temperature.

In addition, the components of the transdermal treatment system of US Patent 6,264,977 B1,

a) layer 1: a backing layer away from the skin,

b) layer 2: at least one active ingredient reservoir,

c) layer 3: active ingredient distribution device associated with the active ingredient reservoir,

d) Layer 4: Devices capable of regulating active substance delivery

It is composed of complex forms.

Japanese Patent JP-A-2002-531488 discloses a transdermal method comprising preparing a coating solution for a silicone adhesive using a low boiling point hexane solvent and applying the solution at low temperature to reduce decomposition or loss of liquid nicotine drugs and the like. The manufacturing method of a patch is described. This method uses a coating at low temperature, but this cannot completely rule out the possibility of nicotine loss, and it is necessary to increase the application amount to obtain the desired amount of nicotine.

In addition, Korean Patent Publication No. 10-2007-0041390 provides a method of excellent content uniformity by adjusting the contact angle of the nicotine and the adhesive layer to 20 ~ 60 ° before applying nicotine.

These transdermal treatment systems have their own useful properties, but there is a need to provide new transdermal treatment systems to improve the complexity, industry and safety of volatilization of nicotine.

Therefore, there has been a demand for the development of a nicotine transdermal therapeutic system in which the active ingredient nicotine does not volatilize and the drug is not released at one time without coating the additional layer for controlling drug release.

Therefore, the inventors have completed the present invention by developing a nicotine transdermal treatment system comprising a single layer and a storage layer composed of a single layer without the release of the drug at a time without the volatilization of nicotine and coating additional layers in the storage layer. It was.

In the present invention, nicotine does not volatilize in the hypolipidemic layer and the drug is not released at one time without coating additional layers, and the dissolution rate is higher than that of the nicotine transdermal treatment system consisting of a novel monolayer and a storage layer. Nicotine transdermal treatment system consisting of more than nicotine transdermal treatment system has the effect that can be mass-produced in a simple way economically.

The present invention relates to a transdermal therapeutic system using nicotine as an active ingredient, and more particularly, to a nicotine patch comprising a single layer of a storage layer having a constant content because of no volatilization of nicotine in the storage layer.

Hereinafter, the present invention will be described in detail.

The configuration of the transdermal treatment system of the present invention,

a) Layer 1: The storage layer is composed of a single layer comprising nicotine as an active ingredient, a skin permeation accelerator, a volatile inhibitor of nicotine and a pressure sensitive adhesive as a polymer, and includes a support capable of supporting the storage layer.

In the present invention, the active snow nicotine may contain 1.0 to 30% by weight based on the entire storage layer.

The volatilization inhibitor of nicotine of the present invention may be used an organic acid or an inorganic acid, and preferably may be any acid that can be present as a liquid without solidifying nicotine as an active ingredient at room temperature. Preferably, acetic acid, oxalic acid, phosphoric acid, lactic acid, methanesulfonic acid, benzoic acid, organic acids having 3 to 8 carbon atoms, or a combination of these acids can be used.

The volatilization inhibitor of nicotine may contain 0.01 to 30% by weight based on the entire storage layer. Acetic acid in the volatile inhibitor of nicotine is adjusted to 0.01 to 20% by weight relative to the weight of the nicotine storage layer as an active ingredient, but may be preferably used at 0.01 to 10% by weight. Even in the case of lactic acid, it is adjusted to 0.01 to 30% by weight relative to the weight of the nicotine storage layer, but may be preferably used to 0.01 to 20% by weight. In the combination of two or more acids, when acetic acid and lactic acid are combined, acetic acid may be used in an amount of 0.01 to 10% by weight and lactic acid in an amount of 0.01 to 20% by weight based on the weight of the nicotine storage layer. In addition, the oxalic acid is adjusted to 0.01 to 20% by weight based on the weight of the nicotine storage layer, but when the oxalic acid is 20% by weight or more, transdermal permeability tends to be lowered. In addition, maleic acid, succinic acid, and tartaric acid having a higher molecular weight than oxalic acid tend to have a significantly lower transdermal permeability if the weight of the nicotine storage layer is 20% by weight or more.

In the present invention, the pressure-sensitive adhesive containing nicotine may be used without any pressure-sensitive adhesive, but is preferably an acrylate polymer with a carboxyl group, an acrylate polymer without a functional group, an acrylate-vinylacetate polymer with a carboxyl group or An acrylate-vinylacetate-based polymer pressure-sensitive adhesive without a functional group may be used. Preferably, Durotak 87-2196 by National Starch is mentioned. Pressure-sensitive adhesive of the present invention is adjusted to 50 to 90% by weight relative to the weight of the storage layer, but more preferably 60 to 80% by weight.

In the present invention, the skin permeation accelerator is a C2-C18 fatty acid ether, nonionic surfactants, isopropyl myristate, transcutol, triacetin, pyrrolidone derivatives, C2-C18 fatty acids, C2-C18 One kind or two or more kinds selected from fatty acid alcohols, fatty acid esters having 2 to 18 carbon atoms, and plasticizers can be used, and span 80 is preferably used among nonionic surfactants. Skin permeation promoter of the present invention is adjusted to 0.1 to 30% by weight based on the weight of the storage layer, but more preferably 1 to 20% by weight.

In the transdermal therapeutic system containing the nicotine of the present invention, the support may be a single layer film such as polyester, polyurethane, polyethylene, polypropylene, polyolefin, polyethylene terephthalate, aluminum treated polyester, or moisture emitted from the human body. In order to prevent the patch from being separated, a non-woven fabric having a moisture absorption ability, a cotton cloth, a fabric, or the like, a multilayer laminate film in which the single layer film is laminated may be used, and any of the drug protection films used in the conventional patch may be used. You may use it.

Hereinafter, the present invention will be described in detail in the Examples. However, the following examples are merely to illustrate the present invention, but not to limit the scope of the present invention.

Example 1

Nicotine 17.5mg, acetic acid 6.69mg, span 80 10mg in a polyacrylate (Duro-Tak 87-2196, National-Starch, USA) 170mg of the storage layer is left at room temperature for 30 minutes to remove air bubbles and then a lab coater , Swiss Mathis Co., Ltd.), cast on a peeling film so that the thickness after drying is about 110㎛, and dried for 3 minutes at 60 ℃ ~ 90 ℃ and cover the support on the storage layer coated on the film and crimped using a roll A patch of 10 cm 2 size was prepared.

Example 2

Nicotine 17.5mg, acetic acid 6.69mg polyacrylate (Duro-Tak 87-2196, National-Starch, USA) 170mg of the storage layer was left at room temperature for 30 minutes to remove the air bubbles (Lab coater, Mathis, Switzerland) Cast on the peeling film so that the thickness after drying to about 110㎛, and dried for 3 minutes at 60 ℃ ~ 90 ℃ and cover the support on the storage layer coated on the film and then compressed using a roll of 10 cm 2 Patches were prepared.

Example 3

Nicotine 17.5mg, lactic acid 9.71mg, span 80 10mg in a polyacrylate (Duro-Tak 87-2196, National-Starch Co., Ltd.) 170mg, the storage layer is left at room temperature for 30 minutes to remove the air bubbles and then a lab coater , Swiss Mathis Co., Ltd.), cast on a peeling film so that the thickness after drying is about 110㎛, and dried for 3 minutes at 60 ℃ ~ 90 ℃ and cover the support on the storage layer coated on the film and crimped using a roll A patch of 10 cm 2 size was prepared.

Example 4

A storage layer dissolved in 170 mg of nicotine 17.5 mg and lactic acid 9.71 mg in polyacrylate (Duro-Tak 87-2196, National-Starch, USA) was left at room temperature for 30 minutes to remove bubbles, followed by a lab coater (Mathis, Switzerland). Cast on the peeling film so that the thickness after drying to about 110㎛, and dried for 3 minutes at 60 ℃ ~ 90 ℃ and cover the support on the storage layer coated on the film and then compressed using a roll of 10 cm 2 Patches were prepared.

Example 5

A coat layer dissolved in 170 mg of nicotine 17.5 mg, oxalic acid 9.71 mg, and span 80 10 mg in polyacrylate (Duro-Tak 87-2196, National-Starch, USA) was left at room temperature for 30 minutes to remove bubbles, and then a lab coater , Swiss Mathis Co., Ltd.), cast on a peeling film so that the thickness after drying is about 110㎛, and dried for 3 minutes at 60 ℃ ~ 90 ℃ and cover the support on the storage layer coated on the film and crimped using a roll A patch of 10 cm 2 size was prepared.

Example 6

Nicotine 18mg, phosphoric acid 12.16mg, Span 80 10mg in a polyacrylate (Duro-Tak 87-2196, National-Starch, USA) 170mg of the storage layer was left at room temperature for 30 minutes to remove the air bubbles and then the lab coater (Lab coater, (Swiss Mathis Co., Ltd.) was cast on the peeling film so that the thickness after drying to about 110㎛, dried for 3 minutes at 60 ℃ ~ 90 ℃, cover the support on the storage layer coated on the film and pressed using a roll 10 A cm 2 patch was prepared.

Example 7

Nicotine 17.5 mg, acetic acid 3.24 mg, lactic acid 4.86 mg, and span 80 10 mg in a 170 mg polyacrylate (Duro-Tak 87-2196, National-Starch, USA) was left at room temperature for 30 minutes to remove bubbles. Using a coater (Lab coater, Mathis, Switzerland) to cast on a peeling film so that the thickness after drying to about 110㎛, dried for 3 minutes at 60 ℃ ~ 90 ℃ and then cover the support on the storage layer coated on the film and roll Press to prepare a patch of 10 cm 2 size.

Comparative Example 1

Commercial nicotine-L (content 17.5 mg) was used as a comparative example.

Comparative Example 2 (Example without Volatilization Inhibitor)

Nicotine 17.5mg, Span80 10mg Polysaccharides (Duro-Tak 87-2196, National-Starch, USA) 170mg of the storage layer was left at room temperature for 30 minutes to remove bubbles, then lab coater (Mathis, Switzerland) Cast on the peeling film so that the thickness after drying to about 110㎛, and dried for 3 minutes at 60 ℃ ~ 90 ℃ and cover the support on the storage layer coated on the film and then compressed using a roll of 10 cm 2 Patches were prepared.

Test Example 1: Content Test

The contents were analyzed by HPLC with Examples 1,2,3,4,5,6,7 and Comparative Example 2, and the results are shown in Table 1.

HPLC operating conditions

Mobile phase: acetate buffer (pH = 4.0): methanol: water = 10: 50: 40

Flow rate: 1.0 ml / min

Wavelength: 260 nm

Injection volume: 10 ul

Column: 150mm X 4.6mm C18 5μm particles

Temperature: 40 ℃

Preparation of Acetate Buffers

Trihydrate Sodium Acetate0.17g

0.30 ml of triethamine

Sodium Dodecyl Sulfate 0.1375 grams

125 ml of acetonitrile

Accurately take the above material into a 500ml flask and distilled water to exactly 500ml and adjust the pH to 4.0 with acetic acid.

Table 1. Nicotine Content in Examples and Comparative Examples

Example Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Comparative Example 2 content(%) 99.8 100.2 99.4 99.6 99.1 99.9 100.1 20.1

As shown in Table 1, the nicotine transdermal drug of the present invention was found to be kept constant, but in Comparative Example 2 in which the volatile inhibitor was not added, it was found that nicotine was volatilized and the content thereof was lowered.

Test Example 2: Dissolution Test

       Comparative Example 2 did not perform the dissolution test because of the low content.

Elution of the transdermal absorbent preparations prepared in Comparative Examples 1, 1, 2, 3, 4, 5, 6 and 7 was evaluated by the Paddle over disk test method of Transdermal Delivery Systems of DRUG RELEASE. The eluate was 500ml, the temperature was 32 ℃, the pH was 7.4 phosphate buffer, the rotational speed was 50rpm, and the samples were taken at 1, 7, and 24 hours. The samples were collected at each time point, and the same volume of eluate was filled. . The dissolution rate of nicotine was analyzed according to the HPLC conditions of the content test of Test Example 1 and the results are shown in FIG. 1.

1 is a graph showing the dissolution rate of nicotine from the transdermal preparations of Comparative Example 1, Examples 1, 2, 3, 4, 5. 6 and 7.

Claims (5)

A nicotine transdermal therapeutic system in which the storage layer is composed of a single layer including nicotine, a skin permeation accelerator, a nicotine volatile inhibitor, and a polymer adhesive, and includes a support. According to claim 1, wherein the storage layer is composed of a single layer containing 1 to 30% by weight of nicotine active ingredient, 0.1 to 30% by weight skin permeation accelerator, 0.01 to 30% by weight of nicotine volatile inhibitor and 50 to 90% by weight of the polymer adhesive And a nicotine transdermal therapeutic system comprising a support. The nicotine transdermium according to claim 1 or 2, wherein the nicotine transdermal agent is composed of a single layer or two or more acids selected from acetic acid, methanesulfonic acid, oxalic acid, lactic acid, phosphoric acid, benzoic acid, and an organic acid having 3 to 8 carbon atoms. Treatment system. The fatty acid ether, nonionic surfactants, isopropyl myristate, transcutol, triacetin, pyrrolidone derivatives, fatty acids having 2 to 18 carbon atoms and 2 carbon atoms as claimed in claim 1 or 2 as a skin permeation accelerator of nicotine. A nicotine transdermal therapeutic system comprising a monolayer having a storage layer comprising one or two or more selected from fatty alcohols of 18 to 18, fatty acid esters of 2 to 18 carbon atoms, and plasticizers. The patch of claim 1 or 2, wherein the support is separated from a monolayer film such as polyester, polyurethane, polyethylene, polypropylene, polyolefin, polyethylene terephthalate, aluminum treated polyester, or moisture released from the human body. Nicotine transdermal therapy system comprising a single layer of a storage layer comprising a support selected from a non-woven fabric, cotton cloth, fabric having a water-absorbing capacity and a multilayer laminate film laminated with the single layer film in order to prevent it.

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