RIVASTIGMINE PATCH FOR LONG-TERM ADMINISTRATION

Abstract

The present invention relates to a patch comprising a high content of rivastigmine per unit area, which can be continuously administered for a long time. The rivastigmine patch according to the present invention is capable of continuous release of rivastigmine for a long period of time, preferably 3 days, more preferably 4 days or more after attachment, and has excellent physical and chemical stability.

Claims

1. A rivastigmine patch for transdermal treatment comprising a backing film; a rivastigmine matrix layer comprising rivastigmine or a pharmaceutically acceptable salt thereof; a self-adhesive matrix layer comprising an adhesive that adheres to the skin; and a release liner that is removed before use, wherein the content per patch area of the rivastigmine or a pharmaceutically acceptable salt thereof is 2 to 15 mg/cm.sup.2 based on the rivastigmine free base, and the rivastigmine matrix layer comprises at least one selected from the group consisting of silicate, microcrystalline cellulose and crospovidone.

2. The rivastigmine patch of claim 1, wherein the content per patch area of the rivastigmine or a pharmaceutically acceptable salt thereof is 3.6 to 10.8 mg/cm2 based on the rivastigmine free base.

3. The rivastigmine patch of claim 2, wherein the content per patch area of the rivastigmine or a pharmaceutically acceptable salt thereof is 5.4 to 9 mg/cm.sup.2 based on the rivastigmine free base.

4. The rivastigmine patch of claim 1, wherein the silicate is magnesium aluminometasilicate, calcium silicate or a mixture thereof.

5. The rivastigmine patch of claim 1, wherein the rivastigmine matrix layer comprises 10-50% by weight of rivastigmine, 10-30% by weight of microcrystalline cellulose, and the residual quantity of an acrylic adhesive based on the total weight of the rivastigmine matrix layer.

6. The rivastigmine patch of claim 1, wherein the rivastigmine matrix layer comprises 10-50% by weight of rivastigmine, 10-30% by weight of magnesium aluminometasilicate, and the residual quantity of an acrylic adhesive based on the total weight of the rivastigmine matrix layer.

7. The rivastigmine patch of claim 1, wherein the rivastigmine matrix layer comprises 10-50% by weight of rivastigmine, 5-25% by weight of crospovidone, and the residual quantity of an acrylic adhesive based on the total weight of the rivastigmine matrix layer.

8. The rivastigmine patch of claim 1, wherein the rivastigmine matrix layer comprises 10-50% by weight of rivastigmine, 2-15% by weight of calcium silicate, and the residual quantity of an acrylic adhesive based on the total weight of the rivastigmine matrix layer.

9. The rivastigmine patch of claim 1, wherein the rivastigmine matrix layer of the patch further comprises an antioxidant.

10. The rivastigmine patch of claim 1, wherein the rivastigmine patch comprises a release controlling membrane which is an ethylene vinyl acetate film between the rivastigmine matrix layer and the self-adhesive matrix layer.

11. The rivastigmine patch of claim 1, wherein the self-adhesive matrix layer comprises a mixture of two or more silicone adhesives having different properties.

12. The rivastigmine patch of claim 11, wherein the self-adhesive matrix layer comprises a mixture of BIO-PSA 7-4201 and 7-4301.

13. The rivastigmine patch of claim 12, wherein the self-adhesive matrix layer comprises a 1:1 weight ratio mixture of BIO-PSA 7-4201 and 7-4301.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0041] FIG. 1 is a graph showing the cumulative permeation percentages of examples of the present invention and a commercially available Exelon™ patch in a permeation test.

[0042] FIG. 2 is a graph showing the cumulative permeation amounts (μg/cm.sup.2) of examples of the present invention and a commercially available Exelon™ patch in a permeation test.

[0043] FIG. 3 is a graph showing changes in permeation rate (μg/cm.sup.2/hour) of examples of the present invention and a commercially available Exelon™ patch in a permeation test.

MODE FOR INVENTION

[0044] Hereinafter, the present disclosure is described in considerable detail with examples to help those skilled in the art understand the present disclosure. However, the following examples are offered by way of illustration and are not intended to limit the scope of the invention. It is apparent that various changes may be made without departing from the spirit and scope of the invention or sacrificing all its material advantages.

[0045] In the following comparative examples and examples, when expressed as simply “%” it means % by weight.

[0046] In the following comparative examples and examples, a PET film was used as a backing film, 3M's Scotchpak 9744 product was used as a release liner, and an ethylene vinyl acetate membrane, 3M CoTran™ 9707 was used as a release-controlling membrane.

[0047] In the following comparative examples and examples, unless otherwise stated, a self-adhesive polysiloxane polymer (Dow Corning® BIO-PSA, 1:1 mixture of 7-4201 and 7-4301) containing 0.1% of DL-alpha-tocopherol was used as a self-adhesive matrix layer.

Comparative Example 1 (4 Day Version of Exelon Patch)

[0048] A patch consisting of (1) a backing film, (2) a self-adhesive matrix layer consisting of 30% by weight of rivastigmine, 20% by weight of plastoid B, 0.1% by weight of DL-alpha-tocopherol, and 49.9% by weight of a self-adhesive acrylic adhesive, (3) a self-adhesive matrix layer consisting of a self-adhesive polysiloxane polymer containing 0.1% by weight of DL-alpha-tocopherol, and (4) a release liner was prepared. It was prepared at 180 GSM (gram per square meter, g/m.sup.2) based on the drug layer (rivastigmine content corresponds to 7.2 mg/cm.sup.2; Exelon™ has 1.8 mg/cm.sup.2/day of rivastigmine content).

Comparative Example 2 (4 Day Version without Matrix Support Material)

[0049] A patch with double-layer system consisting of (1) a backing film, (2) a self-adhesive matrix layer consisting of 40% rivastigmine, 0.1% DL-alpha-tocopherol, and 59.9% self-adhesive acrylic adhesive, (3) a self-adhesive matrix layer consisting of a self-adhesive polysiloxane polymer containing 0.1% DL-alpha-tocopherol, and (4) a release liner was prepared. It was prepared at 180 GSM based on the drug layer (rivastigmine content corresponds to 7.2 mg/cm.sup.2).

Example 1

[0050] A patch with a triple layer system consisting of (1) a backing film, (2) a self-adhesive matrix layer consisting of 40% rivastigmine, 20% microcrystalline cellulose, 0.1% DL-alpha-tocopherol, and 39.9% self-adhesive acrylic adhesive (Duro-Tak® 87-235A), (3) a release-controlling membrane, (4) a self-adhesive matrix layer consisting of a self-adhesive polysiloxane polymer (Dow Corning® BIO-PSA, 1:1 mixture of 7-4201 and 7-4301) containing 0.1% DL-alpha-tocopherol, and (5) a release liner was prepared. It was prepared at 180 GSM based on the drug layer.

Example 2

[0051] A patch with a triple layer system consisting of (1) a backing film, (2) a self-adhesive matrix layer consisting of 40% rivastigmine, 20% Neusilin (UFL2™), 0.1% DL-alpha-tocopherol, and 39.9% self-adhesive acrylic adhesive (Duro-Tak® 87-235A), (3) a release controlling membrane, (4) a self-adhesive matrix layer consisting of a self-adhesive polysiloxane polymer (Dow Corning® BIO-PSA, 1:1 mixture of 7-4201 and 7-4301) containing 0.1% DL-alpha-tocopherol and (5) a release liner was prepared. It was prepared at 180 GSM based on the drug layer.

Example 3

[0052] A patch with a triple layer system consisting of (1) a backing film, (2) a self-adhesive matrix layer consisting of 40% rivastigmine, 15% crospovidone (Kollidone CL-M), 0.1% DL-alpha-tocopherol, and 44.9% self-adhesive acrylic adhesive (Duro-Tak® 87-235A), (3) a release controlling membrane, (4) a self-adhesive matrix layer consisting of a self-adhesive polysiloxane polymer (Dow Corning® BIO-PSA, 1:1 mixture of 7-4201 and 7-4301) containing 0.1% DL-alpha-tocopherol and (5) a release liner was prepared. It was prepared at 180 GSM based on the drug layer.

Example 4

[0053] A patch with a triple layer system consisting of (1) a backing film, (2) a self-adhesive matrix layer consisting of 40% rivastigmine, 5% Florite R, 0.1% DL-alpha-tocopherol, and 54.9% self-adhesive acrylic adhesive (Duro-Tak® 87-235A), (3) a release controlling membrane, (4) a self-adhesive matrix layer consisting of a self-adhesive polysiloxane polymer (Dow Corning® BIO-PSA, 1:1 mixture of 7-4201 and 7-4301) containing 0.1% DL-alpha-tocopherol and (5) a release liner was prepared. It was prepared at 180 GSM based on the drug layer.

Experimental Example 1 (Evaluation of Chemical Stability)

[0054] Stability evaluation of rivastigmine was performed while storing the comparative examples and examples in a room temperature environment and an accelerated environment (40° C., 75% RH) in the following manner.

[0055] Ten round patches of 5 cm.sup.2 size were placed in a 100 mL volumetric flask and diluted with an extraction solvent. After ultrasonic vibration for 60 minutes, 5 mL of this solution was taken at room temperature, put into a 10 mL volumetric flask, and evaporated for 30 minutes under a nitrogen stream. After putting the mobile phase, it was filtered through a 0.45 μm membrane filter.

[0056] Manufacturing of Mobile Phase

[0057] 2.02 g of 1-heptanesulfonate sodium was added to a 1 L volumetric flask, diluted with purified water, and adjusted to pH 3.0 with dilute phosphoric acid. Then, it was filtered through a 0.45 μm membrane filter.

[0058] Preparation of Extraction Solvent

[0059] Methanol:ethyl acetate:triethylamine=70:30:0.4 (V/V/V)

[0060] HPLC Analysis Conditions

[0061] Injection volume: 10 μL

[0062] Column: RP18-C18, 250 mm×4.6 mm, 5 μm

[0063] Detector: UV Detector (217 nm)

[0064] Flow rate: 1.0 mL/min

[0065] Run time: 30 minutes

[0066] Mobile phase: 10 mM Sodium-1-heptane sulphonate buffer:acetonitrile (72:28).

[0067] The results are shown in Table 1 below.

TABLE-US-00001 TABLE 1 Accelerated Environment Long Term Long Term Total Impurities 1 month 3 months 6 months Comparative 0.41% 0.24% 0.35% example 1 Comparative 0.45% 0.30% 0.41% example 2 Example 1 0.50% 0.31% 0.44% Example 2 0.39% 0.19% 0.31% Example 3 0.36% 0.20% 0.47% Example 4 0.58% 0.22% 0.33%

[0068] As shown in Table 1, the rivastigmine patch according to the present invention maintained its stability even if it comprises a high amount of rivastigmine. However, comparatively, when Neusilin or Florite was comprised in the rivastigmine matrix layer, the stability was better than when other materials were used.

Experimental Example 2 (Evaluation of Physical Stability)

[0069] The following physical stability was measured.

[0070] Shear measurement method: After forming a 5 cm.sup.2 circular patch, static shear was measured by connecting a 200 g weight.

[0071] Probe Tack measurement method: After forming a 1.7 cm.sup.2 circular patch, the probe tack was measured.

[0072] Cold flow measurement method: 5 cm.sup.2 circular patch was formed. After pressing with a 1 kg weight for 1 week, the cold flow (creep test) was measured. Alternatively, after leaving it open at 60-80° C. for 1 week, the cold flow was measured.

[0073] The results are shown in Table 2.

TABLE-US-00002 TABLE 2 Shear (Attached area 5 cm.sup.2, Cold flow 200 g) Tack (g) (creep & heat test) Comparative Desorption within 24 >200 g Very severe example 1 hours Comparative Desorption within 1 hour >200 g Very severe example 2 Example 1 72 hours or more 150~200 g Almost none Example 2 72 hours or more 100~150 g Almost none Example 3 72 hours or more 150~200 g Almost none Example 4 72 hours or more 100~150 g Almost none

[0074] As shown in the results of Table 2, the patch according to the present invention showed excellent physical stability.

Experimental Example 3 (Transdermal Penetration of Patch)

[0075] Transdermal penetration experiments using a commercially available Exelon® patch were conducted under the following conditions.

[0076] Franz Diffusion Cell Experimental Parameters

[0077] Apparatus: Hansen Automated Franz diffusion cell sampling system

[0078] Cell volume: 7.0 mL

[0079] Receptor solution: solution phosphate buffered saline (PBS, 1.0 M)

[0080] Dose: 1.8 mg over a 1.0 cm2 area as rivastigmine base; occluded

[0081] Duration: 7 days

[0082] Temperature: 32.5° C.

[0083] Sample volume: 0.9 mL

[0084] Rinse volume: 1.6 mL

[0085] Sample analysis: HPLC

[0086] Membrane: 3M EVA 9715 membrane

[0087] The results are shown in Tables 3 to 6 and FIGS. 1 to 2.

TABLE-US-00003 TABLE 3 Decreasing rate of penetration Flux rate at 1 day Flux rate at 4 day from 24 hours (μg/cm.sup.2/h) (μg/cm.sup.2/h) to 96 hours (%) Exelon ® patch 25~30 μg 0~5 μg 80~90% Examples 1~4 26~32 μg 13~23 μg Within 15~20%

TABLE-US-00004 TABLE 4 Exelon ® Day patch Example 1 Example 2 Example 3 Example 4 0 0.0 0.0 0.0 0.0 0.0 1 53.6 5.7 14.4 10.0 14.4 2 68.9 11.2 22.5 20.0 29.9 3 70.6 15.7 31.3 25.0 33.1 4 72.9 19.7 38.9 5 23.1 6 26.1 51.0 68.6 7 76.0 28.4 54.0 57.0 75.4 Content 1.80 6.13 5.24 7.12 6.64

[0088] Table 4 shows the evaluation results of the cumulative penetration percentage (unit: %).

TABLE-US-00005 TABLE 5 Exelon ® Day patch Example 1 Example 2 Example 3 Example 4 1 965 350 757 670 680 2 1239 685 1179 1310 1390 3 1271 962 1639 1810 1890 4 1312 1209 2038 5 1418 6 1599 3350 3400 7 1367 1741 2829 3720 3740 Content 1.80 6.13 5.24 7.12 6.64

[0089] Table 5 shows the evaluation results of the cumulative penetration amount (μg/cm.sup.2).

TABLE-US-00006 TABLE 6 Exelon ® Day patch Example 1 Example 2 Example 3 Example 4 0.5 40.2 29.9 31.5 27.9 29.7 1.5 11.4 15.7 17.6 26.6 29.6 2.5 1.3 14.1 19.2 20.8 22.0 3.5 1.7 13.5 16.7 22.7 4.5 21.4 5.0 5.5 0.8 11.6 11.0 6.5 15.6 16.0 Content 1.80 6.13 5.24 7.12 6.64

[0090] Table 6 shows the results of Flux rate (μg/cm.sup.2/hour). From the experimental results obtained above, it was confirmed that the examples of the present invention can control the release of the drug continuously during the application period.