RIVASTIGMINE-CONTAINING TRANSDERMAL ABSORPTION PREPARATION

Abstract

The purpose of the present invention is to provide a rivastigmine-containing transdermal absorption preparation having high adhesion to the skin and capable of continuously administering rivastigmine over a long period of time. A transdermal absorption preparation has rivastigmine, a rubber polymer, a tackifier resin, and a polymer compound having a nitrogen-containing group.

Claims

1. A transdermal absorption preparation comprising rivastigmine, a rubber polymer, a tackifier resin, and a polymer compound having a nitrogen-containing group.

2. The transdermal absorption preparation according to claim 1, wherein the nitrogen-containing group is one or more selected from the group consisting of primary, secondary, or tertiary amino groups, imino groups, imide groups, amide groups, and quaternary ammonium groups.

3. The transdermal absorption preparation according to claim 1, wherein the polymer compound having the nitrogen-containing group is a polymer of a (meth)acrylic monomer having the nitrogen-containing group or a vinyl monomer having the nitrogen-containing group, a copolymer of these monomers, a copolymer of at least one of the monomers and a (meth)acrylic monomer having no nitrogen-containing group, or a condensate of polyvinyl alcohol and mono- or dialkylamino acetate.

4. The transdermal absorption preparation according to claim 1, wherein the polymer compound having the nitrogen-containing group is aminoalkyl methacrylate copolymer E.

5. The transdermal absorption preparation according to claim 1, wherein the rubber polymer is one or more selected from the group consisting of styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, styrene-ethylene-butylene-styrene block copolymers, styrene-isoprene rubbers, polyisoprene rubbers, styrene-butadiene rubbers, chloroprene rubbers, liquid rubbers, natural rubber latexes, synthetic latexes, polybutene, polyisoprene, polybutylene, and polyisobutylene.

6. The transdermal absorption preparation according to claim 1, further comprising a cellulose derivative.

7. The transdermal absorption preparation according to claim 6, wherein the cellulose derivative is one or more selected from the group consisting of carboxymethyl cellulose, carmellose sodium, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose.

8. The transdermal absorption preparation according to claim 1, wherein a content of the rivastigmine in the transdermal absorption preparation is 5 mass % or more and 30 mass % or less.

9. The transdermal absorption preparation according to claim 1, wherein a content of the polymer compound having the nitrogen-containing group in the transdermal absorption preparation is 1 mass % or more and 20 mass % or less.

10. The transdermal absorption preparation according to claim 1, wherein a mass ratio of the content of the polymer compound having the nitrogen-containing group to the content of the rivastigmine is 0.05 or more and 4 or less.

Description

EXAMPLES

[0070] Hereinafter, the present invention will be described in further detail with reference to examples below. It should be noted, however, that the present invention is not limited to the following examples, and the variation and the modification of the present invention without departing the gist described above and below are all included the technical scope of the present invention.

Example 1

[0071] 19 g of styrene-isoprene-styrene block copolymer, 14 g of liquid polyisoprene rubber, 33 g of alicyclic saturated hydrocarbon resin (ARKON P100), and 17 g of hydrogenated rosin glycerol ester were mixed and dissolved in a suitable amount of toluene to obtain an adhesive base solution. 5 g of aminoalkyl methacrylate copolymer E was dissolved in 12 g of rivastigmine, the adhesive base solution was then added thereto, and the resultant mixture was stirred and mixed to obtain a homogenous adhesive solution. The obtained adhesive solution was spread on a release layer (PET film), and then the solvent was dried and removed to form an adhesive layer with a thickness of 150 m. Next, a backing (PET film) was bonded to the adhesive layer to obtain a patch. The content of each component was shown in Table 1.

Examples 2 to 7

[0072] Each of the patches of Examples 2 to 7 was obtained by the same production method as in Example 1 except that hydroxypropyl methyl cellulose was added together with the adhesive base solution, the content of each component was changed as shown in Table 1, and the thickness of the adhesive layer was changed to the thickness shown in Table 1.

Comparative Example 1

[0073] The patch of Comparative Example 1 was obtained by the same production method as in Example 1 except that aminoalkyl methacrylate copolymer E was not added, and the content of each component was changed as shown in Table 1.

Comparative Example 2

[0074] The patch of Comparative Example 2 was obtained by the same production method as in Example 5 except that 2-ethylhexyl acrylate-vinyl acetate-2-hydroxyethyl acrylate copolymer (DURO-TAK 87-4287), which is an acrylic adhesive agent, was used instead of aminoalkyl methacrylate copolymer E.

Comparative Example 3

[0075] The patch of Comparative Example 3 was obtained by the same production method as in Example 5 except that butyl methacrylate-methyl methacrylate copolymer (PLASTOID B), which is an excipient, was used instead of aminoalkyl methacrylate copolymer E. Like aminoalkyl methacrylate copolymer E, Plastoid B is solid at normal temperature and is one of polymers used as a coating agent or a binder.

Comparative Example 5

[0076] 15 g of styrene-isoprene-styrene block copolymer and 28 g of liquid paraffin were mixed and dissolved in a suitable amount of toluene to obtain an adhesive base solution. 7 g of rivastigmine was added to the adhesive base solution, and the resultant mixture was stirred and mixed to obtain a homogenous adhesive solution. The obtained adhesive solution was spread on a release layer (PET film), and then the solvent was dried and removed to form an adhesive layer with a thickness of 128.6 m such that the content of rivastigmine in the adhesive layer after drying was 1.8 mg/cm.sup.2. Next, a backing (PET film) was bonded to the adhesive layer to obtain a patch of Comparative Example 5. Comparative Example 5 was produced with reference to Example 3 of Patent Document 1 (WO 2013/187451).

Comparative Example 6

[0077] 19.5 g of styrene-isoprene-styrene block copolymer, 18 g of alicyclic saturated hydrocarbon resin (ARKON P100), and 5.5 g of polybutene were mixed and dissolved in a suitable amount of toluene to obtain an adhesive base solution. The adhesive base solution was added to 7 g of rivastigmine, and the resultant mixture was stirred and mixed to obtain a homogenous adhesive solution. The obtained adhesive solution was spread on a release layer (PET film), and then the solvent was dried and removed to form an adhesive layer with a thickness of 85 m such that the content of rivastigmine in the adhesive layer after drying was 1.2 mg/cm.sup.2. Next, a backing (PET film) was bonded to the adhesive layer to obtain a patch of Comparative Example 6. Comparative Example 6 was produced with reference to Example 1 of Patent Document 2 (JP 2014-508728 A).

Adhesion Test: Probe Tack Test

[0078] In order to compare the adhesions of Examples 1 to 7 and Comparative Examples 1 to 3, 5, and 6, a probe tack test was performed. First, a test preparation was prepared by cutting the preparation of each of the Examples and the Comparative Examples into a circle with a diameter of 14 mm. Next, a double-sided tape was affixed on a sample stage of a rheometer, and the test preparation was affixed on the sample stage with the PET film facing upward. Then, after attaching a stainless steel disk-shaped probe (diameter: 5 mm) to a pressure-sensitive shaft attachment, the PET film was peeled from the test preparation, and the sample stage was raised at a rate of 10 mm/min. Finally, the adhesive surface was brought into contact with the probe with a force of 50 g and left still for 10 seconds, and then a force required to pull the adhesive surface apart was measured to obtain a tack force (g). The results are shown in Table 1.

Finger Tack Test (Sensory Evaluation)

[0079] In order to sensorially evaluate the tackiness of each of Examples 1 to 7 and Comparative Examples 1 to 3, 5, and 6, a finger tack test was performed. Specifically, a finger was pressed against a surface of the adhesive layer, and tackiness (adhesive strength) when the finger was pulled apart was evaluated. The patches having a high adhesive strength were evaluated as being excellent (), the patches having a medium adhesive strength were evaluated as being good (), and the patches having a low adhesive strength were evaluated as being poor (). The results are shown in Table 1.

TABLE-US-00001 TABLE 1 Example Example Example Example Example Example Example 1 2 3 4 5 6 7 Main drug Rivastigmine mass % 12 12 12 13 13 13 13 Rubber Styrene-isoprene-styrene block mass % 19 18.5 20 19.2 19 18.7 18.4 polymer copolymer Liquid polyisoprene rubber mass % 14 14 13.5 13 13 13 13 Polybutene mass % Tackifier Alicyclic saturated mass % 33 33.3 26 32.2 32 31.5 31.1 resin hydrocarbon resin Hydrogenated rosin glycerol mass % 17 16.7 18 17.1 17 16.8 16.5 ester Aminoalkyl methacrylate copolymer E mass % 5 5 10 5 5 5 5 2-ethylhexyl acrylate-vinyl acetate-2- mass % hydroxyethyl acrylate copolymer (Duro-tak 87-4287) Butyl methacrylate-methyl methacrylate mass % copolymer (Plastoid B) Hydroxypropyl methyl cellulose mass % 0.5 0.5 0.5 1 2 3 Liquid Paraffin mass % Thickness of the adhesive layer (m) 150 150 150 138.5 138.5 138.5 138.5 Tack force (g) 662 687.5 705.8 721.8 850.5 708.2 718.7 Finger Tack Test results Comparative Comparative Comparative Comparative Comparative Example Example Example Example Example 1 2 3 5 6 Main drug Rivastigmine mass % 12 13 13 14 14 Rubber Styrene-isoprene-styrene block mass % 20 19 19 30 39 polymer copolymer Liquid polyisoprene rubber mass % 14 13 13 Polybutene mass % 11 Tackifier Alicyclic saturated mass % 36 32 32 36 resin hydrocarbon resin Hydrogenated rosin glycerol mass % 18 17 17 ester Aminoalkyl methacrylate copolymer E mass % 2-ethylhexyl acrylate-vinyl acetate-2- mass % 5 hydroxyethyl acrylate copolymer (Duro-tak 87-4287) Butyl methacrylate-methyl methacrylate mass % 5 copolymer (Plastoid B) Hydroxypropyl methyl cellulose mass % 1 1 Liquid Paraffin mass % 56 Thickness of the adhesive layer (m) 150 138.5 138.5 128.6 85 Tack force (g) 445.9 353.4 373.5 162.3 495.7 Finger Tack Test results x x x x

[0080] The following can be considered from Table 1.

[0081] Example 1, which satisfies the requirements of the present invention, had a higher tack force than the tack forces of Comparative Examples 1 to 3, 5, and 6. Furthermore, in Examples 2 to 7, due to the addition of hydroxypropyl methyl cellulose, the synergistic effect of hydroxypropyl methyl cellulose and aminoalkyl methacrylate copolymer E was exhibited, the tack force was further increased, and excellent results were also obtained in the finger tack test. From this fact, it is considered that the preparation of the present invention has excellent skin adhesion.

In Vitro Skin Permeability Test

[0082] To examine the transdermal absorbability of rivastigmine in each of Example 5 and Comparative Example 4 (commercially available rivastigmine-containing patch (EXELON (registered trademark) patch)), an in vitro skin permeability test was performed. First, an excised dorsal skin of a white male was treated so as to have a thickness of 750 m, and then put on a Franz diffusion cell. Each preparation cut in a round shape with a diameter of 14 mm was applied to this skin. The receptor side was filled with phosphate buffered saline (pH 7.5), and warm water of 37 C. was circulated in the water jacket. The receptor solution was sampled with time, the amount of rivastigmine that permeated the skin was measured by a liquid chromatography. From the measurement results, the cumulative drug permeation amount (g/cm.sup.2) after 24 hours from the start of the test and the maximum value of a drug absorption rate (flux: g/cm.sup.2/hour) were calculated. The results are shown in Table 2.

TABLE-US-00002 TABLE 2 Cumulative drug permeation Maximum amount after value of 24 hours from a drug the start of absorption the test rate (g/cm.sup.2) (g/cm.sup.2/hour) Example 5 789.2 50.4 Comparative 737.8 50.4 Example 4

[0083] The following can be considered from Table 2.

[0084] Example 5, which satisfies the requirements of the present invention, as compared with Comparative Example 4 (commercially available rivastigmine-containing patch), had a similar maximum value of the drug absorption rate but had a higher cumulative drug permeation amount after 24 hours from the start of the test. This showed that that the preparation of the present invention exhibited a transdermal absorbability superior to that of the commercially available product. In the preparation of Example 5 after 24 hours from the start of the test, no lifting or peeling was observed.