KR101175925B1 - A simple transdermal composition of rivastigmine - Google Patents

Abstract

The present invention relates to a transdermal absorbent comprising an active ingredient rivastigmine and a salt thereof for treating dementia, and more particularly, to a rivastigmine patch, which is composed of a two-layered support layer and a storage layer. Provide an absorbent.

Rivastigmine, dementia, percutaneous absorption, patch

Description

A simple transdermal composition of rivastigmine

The present invention relates to a rivastigmine patch comprising rivastigmine and a salt thereof, which is a treatment for dementia, and provides a simple transdermal absorbent comprising two layers, a support layer and a storage layer.

Rivasstigmine tartarate is a drug used for the treatment of dementia (trade name: EXELON) and is commercially available in tablets and suspensions. In addition, as a transdermal absorbent, it is marketed as an Exelon Patch using rivastagmine free base as an active ingredient. Exelon patches are commercially available in sizes of 10 cm 2 (active ingredient: 18 mg) and 5 cm 2 (active ingredient: 9 mg).

WO 99/34782 describes transdermal absorbers based on rivastigmine free base. WO 99/34782 used antioxidants such as tocopherol acetate, ascorbyl palmitate and ascorbic acid to stabilize rivastigmine free base, preferably alpha-tocopherol. Or a method of stabilizing the formulation using 0.01 to 0.15% of palmitic acid ascorbic acid.

In addition, the components of the transdermal absorbent of WO 99/34782,

a) layer 1: polymethacrylate backing layer

b) layer 2: acrylate copolymer comprising rivastigmine free base

c) Layer 3: BIO-PSA Q7-4302 Silicone Adhesive Layer

d) Layer 4: A four-layer structure consisting of release-liners in a complex form.

WO 99/34782 goes through a complex process of coating layer 3 (BIO-PSA Q7-4302 silicone adhesive layer) to control the release of rivastigmine into the skin.

In addition, the components of Korean Patent Publication No. 10-2008-0071581,

a) layer 1: back layer

b) Layer 2: storage layer comprising rivastigmine free base and polymer

c) Layer 3: A transdermal absorbent consisting of a silicone polymer and an adhesive layer is described.

Republic of Korea Patent Publication No. 10-2008-0071581 also has a complex system to control the drug release by coating a silicone adhesive layer. In summary, the manufacturing process

a) preparing the active ingredient in the adhesive solution,

b) coating the active ingredient in an adhesive solution,

c) drying the active ingredient in the adhesive solution,

d) preparing a silicone adhesive solution,

e) coating a silicone adhesive solution,

f) laminating a silicone adhesive layer to the drug in the adhesive layer,

g) It has a complicated process of punching and pouching.

In general, when the active ingredient is a liquid such as rivastigmine, in order to achieve the mechanical processability of the polymer, so-called “thickening polymer” (Plastoid B) should be used in a large amount, but it is the adhesive property of the transdermal absorbent. There is a disadvantage that causes. In Korean Patent Publication No. 10-2008-0071581, in order to compensate for this disadvantage, the application of a silicone adhesive line to a poorly adhesive storage matrix prevents the release of active ingredients from the matrix and the skin without affecting the thermodynamic properties of the transdermal absorbent. A method is described that significantly increases the adhesion properties of a formulation without reducing its penetration through. It is also described a method of coating the silicone lines such that the penetration of the active ingredient through the skin from the storage layer to 40% or less, particularly preferably 10% or less, prevents the active ingredient from penetrating at once.

These transdermal absorbents have their own useful properties, but there is a need to provide transdermal absorbents to improve the complexity, industry and stability of the process for controlling drug release.

Accordingly, the present invention provides a novel rivastigmine transdermal absorbent that prevents drug release at one time without coating additional layers, such as silicone adhesive lines.

Accordingly, the present inventors have completed the present invention by developing a two-layered rivastigmine transdermal absorbent which allows the drug to be released constantly using a drug release control agent without coating an additional layer such as a line of silicone adhesive.

The present invention is to prepare a transdermal absorbent composed of a two-stage simple process of allowing the drug to be constantly released without coating an additional layer such as a silicone line to control the drug release of the transdermal absorbent using the active ingredient rivastigmine, a dementia treatment can do.

The present invention relates to a transdermal absorbent comprising rivastatin as an active ingredient, and more particularly, to a ribistigmine patch composed of two layers.

Hereinafter, the present invention will be described in detail.

The structure of the transdermal absorbent of the present invention,

a) layer 1: backing layer which is a backing layer

b) Layer 2: It consists of two layers which are a storage layer containing an active ingredient rivastigmine free base, a skin permeation promoter, a drug release control agent, and a polymer adhesive.

In the transdermal absorbent containing rivastigmine of the present invention, the support is thin, flexible, and does not cause an allergic reaction to the skin, in order to prevent the loss of rivastigmine from the formulation during attachment or storage to the skin. use. The support may be a single layer film such as polyester, polyurethane, polyethylene, polypropylene, polyolefin, polyethylene terephthalate, aluminum treated polyester, or water absorbing ability to prevent the patch from being released by moisture emitted from the human body. Non-woven fabrics, cotton fabrics, fabrics and the like laminated multilayer film laminated the single layer film may be used, and any of the drug protection film used in the conventional patching agent may be used.

In the present invention, the pressure-sensitive adhesive containing rivastigmine may be used without any pressure-sensitive pressure-sensitive adhesive, but is preferably an acrylate polymer with a hydroxyl group, an acrylate polymer without a functional group, an acrylate with a hydroxyl group. Vinylacetate-based polymers or acrylate-vinylacetate-based polymer pressure-sensitive adhesives without functional groups may be used. Preferably, Durotak 87-2196 by National Starch is mentioned.

In the present invention, the skin permeation promoter is selected from the group consisting of fatty acid ethers, nonionic surfactants, isopropyl myristate, transcutol, triacetin, pyrrolidone derivatives, fatty acids, fatty acid alcohols, fatty acid esters and plasticizers. Can be used. 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. If the skin permeation accelerator is more than 30% by weight, the skin permeability is no longer improved, and further, the physical strength of the patch may be lowered.

The drug release modulator 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 the active ingredient rivastigmine at room temperature. Preferably acetic acid, methanesulfonic acid, oxalic acid, phosphoric acid, lactic acid or a combination of these acids. Acetic acid is adjusted to 0.01 to 2 equivalents based on 1 equivalent of rivastigmine as the active ingredient, but preferably 0.01 to 1 equivalent. If acetic acid is more than 2 equivalents, the commodity is inferior due to the smell of acetic acid. In addition, when combining acetic acid and methanesulfonic acid, 0.01-0.9 equivalents of acetic acid and 0.01-0.5 equivalents of methanesulfonic acid can be used with respect to 1 equivalent of rivastigmine. The use of more than 0.5 equivalents of methanesulfonic acid leads to the disadvantage that rivastigmine is semi-solid and inferior in processability. In addition, in the case of oxalic acid is adjusted to 0.01 to 1 equivalent to 1 equivalent of rivastigmine, preferably can be used in 0.01 to 0.5 equivalents, there is a disadvantage that the transdermal permeability is significantly lowered if oxalic acid is 1 equivalent or more.

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

Example 1

A storage layer dissolved in 74.02 mg of rivastigmine 18 mg, acetic acid 4.32 mg, and alpha-monoisostearyl glyceryl ether in 74.02 mg of polyacrylate (Duro-Tak87-2196, National-Starch, USA) was left at room temperature for 30 minutes. After removing the air bubbles, using a lab coater (Mathis, Switzerland), cast on a peeling film so that the thickness after drying to 62㎛, dried at 90 ℃ for 10 minutes and then cover the support on a storage layer coated on the film and roll Press to prepare a patch (10 cm 2).

Example 2

A storage layer of 76.18 mg of rivastigmine 18 mg, acetic acid 2.16 mg, and alpha-monoisostearyl glyceryl ether in 76.18 mg of polyacrylate (Duro-Tak87-2196, National-Starch, USA) was left at room temperature for 30 minutes. After removing the air bubbles, using a lab coater (Mathis, Switzerland), the film was cast on a peeling film to have a thickness of 60 μm after drying, dried at 90 ° C. for 10 minutes, and then covered with a support on a storage layer coated on the film and rolled. Press to prepare a patch (10 cm 2).

Example 3

A storage layer dissolved in 71.43 mg of rivastigmine 18 mg, methanesulfonic acid 6.91 mg, and alpha-monoisostearyl glyceryl ether in 71.43 mg of polyacrylate (Duro-Tak87-2196, National-Starch, USA) was left at room temperature for 30 minutes. After removing the air bubbles by using a lab coater (Mathis, Switzerland) cast on the peeling film so that the thickness after drying to 64㎛, dried at 90 ℃ for 10 minutes and then covered the support on the storage layer coated on the film Compression was performed using a roll to prepare a patch (10 cm 2).

Example 4

A storage layer was dissolved in 74.62 mg of polyacrylate (Duro-Tak87-2196, National-Starch, USA) with 18 mg of rivastigmine, 3.02 mg of acetic acid, 0.69 mg of methanesulfonic acid, and 6.42 mg of alpha-monosisos tearyl glyceryl ether. After leaving for 30 minutes at room temperature to remove the air bubbles, using a lab coater (Mathis, Switzerland) cast a film on the peeling film after drying to 61㎛, dried at 90 ℃ for 10 minutes and then coated on the film A patch (10 cm 2) was prepared by covering the support on the layer and pressing using a roll.

Example 5

A storage layer dissolved in 75.1 mg of rivastigmine 18 mg, oxalic acid 3.24 mg, and alpha-monoisostearyl glyceryl ether in 75.1 mg of polyacrylate (Duro-Tak87-2196, National-Starch, USA) was left at room temperature for 30 minutes. After removing the air bubbles, using a lab coater (Mathis, Switzerland), the film was cast on a peeling film to have a thickness of 63 μm after drying, dried at 90 ° C. for 10 minutes, and then covered with a support on a storage layer coated on the film and rolled. Press to prepare a patch (10 cm 2).

Example 6

A storage layer dissolved in 75.1 mg of rivastigmine 18 mg, lactic acid 3.24 mg, and alpha-monoisostearyl glyceryl ether in 75.1 mg of polyacrylate (Duro-Tak87-2196, National-Starch, USA) was left at room temperature for 30 minutes. After removing the air bubbles, using a lab coater (Mathis, Switzerland), the film was cast on a peeling film to have a thickness of 63 μm after drying, dried at 90 ° C. for 10 minutes, and then covered with a support on a storage layer coated on the film and rolled. Press to prepare a patch (10 cm 2).

Comparative Example 1

Commercial accelerators (18 mg) were used as comparative examples.

Comparative Example 2 (Example of Drug Release Regulator)

A storage layer dissolved in 78.33 mg of rivastigmine 18 mg and alpha-monoisostearyl glyceryl ether in polyacrylate (Duro-Tak87-2196, National-Starch, USA) was left at room temperature for 30 minutes to remove bubbles. Using a lab coater (Mathis, Switzerland), the film is cast on a peeling film to have a thickness of 60 μm after drying, dried at 90 ° C. for 10 minutes, covered with a support on a storage layer coated on the film, and then compressed using a roll. To prepare a patch (10 cm 2).

Test Example 1: Transdermal Permeation Test

The transdermal absorbent of Example 3 did not undergo a transdermal permeation test because the contents of the storage layer did not transfer to the support layer.

Drug absorption of the transdermal absorbents prepared in Comparative Examples 1 and 2, Examples 1, 2, 4, 5, and 6 was evaluated by extracting (3 × 3 cm 2) of a hairless mouse (Hairless mouse, female, 6 weeks old) It was. The skin permeability test was performed using a Franz type diffusion cell having a diffusion region of 1.77 cm 2. The volume of the chamber solution was 12.5 mL. Patches prepared in Control Examples and Examples 1, 2, 4, 5 and 6 were pressed against the extracted white rat skin against the patch formulation, and the skin / patch stack was pressed against the surface of the Franz cell. The clamp was fixed between the supply chamber and the receiving chamber. Phosphate buffer solution (pH 7.4) was added to the chamber of Franz Cell, and the temperature of the diffusion apparatus was maintained at 32 ° C. The buffer solution of the receptor was stirred at a constant speed of 600 rpm, 0.2 mL of sample was taken from the receptor at each time point, and the same volume of fresh phosphate buffered saline was added to maintain the sink condition. The amount of rivastigmine permeated through the skin was analyzed under HPLC conditions and shown in FIG. 1.

HPLC operating conditions

Mobile phase: Methanol-0.02M ammonium acetate = 55: 45 (v / v)

Flow rate: 1.0 ml / min

Wavelength: 217 nm

Injection volume: 10 ul

Column: 250mm X 4.6mm C18 5μm particles

Temperature: 35 ℃

Test Example 2: Stability Test

The transdermal absorbents prepared in Comparative Examples 1, 2, and Example 1 were stored at 40 ± 2 ° C. and RH 70 ± 5 ° C. for 60 days for stability tests. The stability test was performed according to the transdermal permeation HPLC operation conditions of Test Example 1, and the HPLC results of Comparative Example 1 are shown in FIG. 2, and the HPLC results of Comparative Example 2 are shown in FIG. 3, and the results of Example 1 are shown in FIG. And the result of Example 2 is shown in FIG. 5, and the result of Example 4 is shown in FIG.

No other impurities were produced in Comparative Example 1 with the transdermal absorbent of the present invention on HPLC, but in Comparative Example 2, it was confirmed that impurities were generated at a retention time of about 7.5 minutes. It was found to be maintained.

 1 is a graph showing the accumulation amount of rivastigmine from the transdermal absorbents of Comparative Examples 1 and 2, Examples 1, 2, 4, 5 and 6,

 2 is a HPLC picture after 60 days stability test of Comparative Example 1,

 3 is a HPLC picture after 60 days stability test of Comparative Example 2,

 Figure 4 is an HPLC picture after 60 days stability test of Example 1,

 Figure 5 is an HPLC picture after 60 days stability test of Example 2,

 Figure 6 is an HPLC picture after 60 days stability test of Example 4.

Claims (6)

a) layer 1: backing layer which is a backing layer b) Layer 2: Two-layer rivastigmine transdermal absorbent consisting of a storage layer comprising rivastigmine, a skin permeation accelerator, a drug release control agent and an acrylate-based polymer adhesive. The skin permeation accelerator according to claim 1, wherein the skin permeation accelerator is selected from the group consisting of fatty acid ethers, nonionic surfactants, isopropyl myristate, transcutol, triacetin, pyrrolidone derivatives, fatty acids, fatty alcohols and fatty acid esters. Rivastigmine transdermal absorbent. The two-layered rivastigmine transdermal absorbent according to claim 2, wherein the skin permeation accelerator comprises alpha-monoisostearyl glyceryl ether as fatty acid ethers. The two-layer rivastigmine transdermal absorbent according to claim 1, comprising an acid selected from organic acids or inorganic acids as drug release control agents. The two-layer rivastigmine transdermal absorbent according to claim 4, wherein the acid comprises one or two or more acids selected from acetic acid, methanesulfonic acid, oxalic acid, lactic acid, and phosphoric acid. The method of claim 1, wherein the support is laminated with a single layer film of polyester, polyurethane, polyethylene, polypropylene, polyolefin, polyethylene terephthalate, aluminum treated polyester, and a single layer film of nonwoven fabric, cotton cloth, fabric, or these single layer films. A two layer rivastigmine transdermal absorbent comprising using a support selected from one multilayer laminate film.

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