ASENAPINE-CONTAINING ADHESIVE PATCH

Abstract

An object of the present invention is to provide an asenapine-containing patch having excellent adhesiveness and handleability, which can persistently provide sufficient medicinal effects by suppressing cold flow during storage or application while enhancing skin permeability using a silicone-based pressure-sensitive adhesive base, and thereby maintaining the stability of the drug in the patch during storage, and maintaining an appropriate administration form for a long period of time. The present invention relates to a patch having a support and a pressure-sensitive adhesive layer, wherein the pressure-sensitive adhesive layer comprises asenapine and a silicone-based pressure-sensitive adhesive base, and the loss tangent (tan δ) of the pressure-sensitive adhesive layer is 0.75 to 1.5 at 1.0 Hz.

Claims

1. A patch comprising a support and a pressure-sensitive adhesive layer, wherein the pressure-sensitive adhesive layer comprises asenapine and/or a pharmaceutically acceptable salt thereof, and a silicone-based pressure-sensitive adhesive base, and wherein a loss tangent (tan δ) of the pressure-sensitive adhesive layer is 0.75 to 1.5 at 1.0 Hz.

2. The patch according to claim 1, wherein the pressure-sensitive adhesive layer has a viscosity of 3,000 to 60,000 Pa s at 90° C.

3. The patch according to claim 1, wherein the pressure-sensitive adhesive layer has a viscosity of 3,500 to 60,000 Pa s at 90° C.

4. The patch according to claim 1, wherein the silicone-based pressure-sensitive adhesive base comprises at least one selected from the group consisting of high-tack amine-compatible silicone-based pressure-sensitive adhesive bases, medium-tack amine-compatible silicone-based pressure-sensitive adhesive bases and low-tack amine-compatible silicone-based pressure-sensitive adhesive bases.

5. The patch according to claim 4, wherein the silicone-based pressure-sensitive adhesive base comprises a high-tack amine-compatible silicone-based pressure-sensitive adhesive base and a medium-tack amine-compatible silicone-based pressure-sensitive adhesive base.

6. The patch according to claim 5, wherein the mass ratio of the high-tack amine-compatible silicone-based pressure-sensitive adhesive base to the medium-tack amine-compatible silicone-based pressure-sensitive adhesive base is 90:10 to 10:90.

7. The patch according to claim 4, wherein the silicone-based pressure-sensitive adhesive base comprises a high-tack amine-compatible silicone-based pressure-sensitive adhesive base and a low-tack amine-compatible silicone-based pressure-sensitive adhesive base.

8. The patch according to claim 7, wherein the mass ratio of the high-tack amine-compatible silicone-based pressure-sensitive adhesive base to the low-tack amine-compatible silicone-based pressure-sensitive adhesive base is 90:10 to 30:70.

9. The patch according to claim 1, wherein the pressure-sensitive adhesive layer is composed of asenapine and a silicone-based pressure-sensitive adhesive base.

10. The patch according to claim 1, wherein the pressure-sensitive adhesive layer further comprises an antioxidant.

11. The patch according to claim 10, wherein the pressure-sensitive adhesive layer is composed of asenapine, a silicone-based pressure-sensitive adhesive base, and an antioxidant.

12. The patch according to claim 10, wherein the antioxidant is at least one selected from the group consisting of dibutylhydroxytoluene, mercaptobenzimidazole, ethylenediaminetetraacetic acid and citric acid.

13. The patch according to claim 1, wherein the mass of the pressure-sensitive adhesive layer is 30 to 200 g/m.sup.2.

Description

EXAMPLES

Example 1. Preparation of Patch (High Tack+Medium Tack)

[0052] Patches 1 to 7 were prepared according to the composition shown in Table 1. The mass of the pressure-sensitive adhesive was 100 g/m.sup.2 (set value).

TABLE-US-00001 TABLE 1 Patch Component 1 2 3 4 5 6 7 Asenapine (free form) 3.2 3.2 3.2 3.2 3.2 3.2 3.2 Silicone PSA-4202 96.8 84.7 72.6 48.4 24.2 12.1 0 Silicone PSA-4302 0 12.1 24.2 48.4 72.6 84.7 96.8 Total 100 100 100 100 100 100 100 PSA-4202:PSA-4302 100:0 87.5:12.5 75:25 50:50 25:75 12.5:87.5 0:100 PSA-4202: BIO-PSA ® 7-4202 Silicone Adhesive (Dow Corning Corp.) PSA-4302: BIO-PSA ® 7-4302 Silicone Adhesive (Dow Corning Corp.)

Example 2. Dynamic Viscoelasticity Test

[0053] Using patches 1, 3 to 7 as a sample, the loss elastic modulus and the storage elastic modulus were measured under the following conditions, and the loss tangent (tan δ value) was calculated (N=1 or 2).

[Measurement Conditions]

Equipment: HAAKE MARS III (Thermo Fisher Scientific Inc.)

[0054] Sample part: Parallel flat plates with 8-mm diameter
Gap spacing: 1 mm
Sample amount: 130 mg±10 mg

Temperature: 32° C.

Frequency: 1 Hz

Distortion: 1%

[0055] Table 2 shows the results of calculating the loss tangent (tan δ value) from the values of storage elastic modulus and loss elastic modulus obtained by the dynamic viscoelasticity test.

TABLE-US-00002 TABLE 2 Patch 1 3 4 5 6 7 tan δ value 0.90 0.94 1.08 1.28 1.41 1.48

Example 3. Viscosity Measurement

[0056] The viscosities of patches 1, 3 to 7 at 90° C. were measured using a flow tester (Shimadzu Corporation, product name “FLOWTESTER CFT-500”) under the following measurement conditions (N=2). The results are shown in Table 3.

[Measurement conditions]
Temperature rise: 5.0° C./min
Die hole diameter: 0.5 mm
Die length: 1.0 mm
Test weight: 50.0 kg

TABLE-US-00003 TABLE 3 Patch 1 3 4 5 6 7 Viscosity 52215 19735 10274 5730.5 4289.5 3161.0 (Pa.Math. s)

Example 4. Cold Flow Evaluation Test

[0057] After applying a weight of 1 kg on patches 3 to 6 (circular, 2.49 cm.sup.2) (cold flow induction), the patches were stored in a thermo-hygrostat at 32° C. and 60% RH for 48 hours, and the cold flow area ratio (percentage of the area of the cold flow portion relative to the area with no cold flow (circular, 2.49 cm.sup.2)) was calculated (N=3). The results are shown in Table 4.

TABLE-US-00004 TABLE 4 Patch 3 4 5 6 Cold flow area ratio (%) 2.95 6.04 7.86 13.63

[0058] The cold flow area ratios of the patches 3 to 6 were all less than 15% and good results were obtained. In addition, the cold flow area ratios of the patches 3 to 5 were all less than 10%, and even better results were obtained.

Example 5. Temporal Stability Test

[0059] Patches 8 to 17 were prepared according to the composition shown in Table 5.

TABLE-US-00005 TABLE 5 Patch 8 9 10 11 12 13 14 15 16 17 Asenapine maleate 6 6 6 6 6 6 6 6 6 6 Silicone PSA-4202 89.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 88.1 Dibutylhydroxytoluene — 1 — — — — — — — — Butylhydroxyanisole — — 1 — — — — — — — Ascorbic acid — — — 1 — — — — — — Tocopherol — — — — 1 — — — — — Sodium pyrosulphite — — — — — 1 — — — — Mercaptobenzimidazole — — — — — — 1 — — — Ethylenediamine — — — — — — — 1 — — tetraacetic acid 1,3-Butylene glycol — — — — — — — — 1 — Citric acid — — — — — — — — — 1 Other components 4.9 4.9 4.9 4.9 4.9 4.9 4.9 4.9 4.9 4.9 Total 100 100 100 100 100 100 100 100 100 100

[0060] Patches 8 to 17 are individually packaged in an aluminum bag, and asenapine analogs were measured at immediately after production and after storage at 60° C. for 2 weeks (60° C.2W), under the following measurement conditions using high performance liquid chromatography (HPLC). The results are shown in Table 6.

[Measurement conditions]
Column: ODS column
Mobile phase solution: Methanol/(0.01 mol/L sodium lauryl
sulfate in 0.1% phosphate solution)=3/1
Detection wavelength: 230 nm

[0061] The numbers in parentheses in the table indicate the relative retention time RRT of an arbitrary analog, which is calculated as follows.

[Relative retention time of arbitrary analog (RRT)]=[Retention time of peak of arbitrary analog (RT)]÷[Retention time of peak of asenapine (RT)]

[0062] In addition, the amount of analog (%) is calculated as follows.

[Amount of analog (%)]=[Peak area of arbitrary analog]÷[Peak area of asenapine]×100

TABLE-US-00006 TABLE 6 Analog A, RRT(0.59) Analog B, RRT(1.13) Analog C, RRT(2.07) Just after 60° C. Just after 60° C. Just after 60° C. Patch production 2 W production 2 W production 2 W 8 0.188 0.084 0.000 0.557 0.000 0.053 9 0.135 0.000 0.000 0.158 0.000 0.000 10 16.142 15.958 0.146 1.712 0.041 0.086 11 0.238 0.176 1.684 2.858 0.000 0.000 12 0.000 0.000 0.000 1.392 0.067 0.000 13 0.000 0.000 1.101 0.000 0.000 0.000 14 0.000 0.000 0.000 0.000 0.000 0.054 15 0.000 0.000 0.193 0.307 0.000 0.000 16 0.000 0.000 0.291 1.403 0.000 0.000 17 0.000 0.000 0.040 0.476 0.000 0.000

[0063] Patch 9 (containing dibutylhydroxytoluene), patch 14 (containing mercaptobenzimidazole), patch 15 (containing ethylenediaminetetraacetic acid) and patch 17 (containing citric acid) have relatively low asenapine analogs compared to patch 8, indicating that asenapine was more stable.

Example 6. Preparation of Patch (High Tack+Low Tack)

[0064] Patches 18 to 25 were prepared according to the composition shown in Table 7. The mass of the pressure-sensitive adhesive was 100 g/m.sup.2 (set value).

TABLE-US-00007 TABLE 7 Patch Component 18 19 20 21 22 23 24 25 Asenapine (free form) 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 Silicone PSA-4102 96.8 84.7 72.6 48.4 24.2 12.1 0 0 Silicone PSA-4302 0 12.1 24.2 48.4 72.6 84.7 96.8 91.8 Silicone oil 0 0 0 0 0 0 0 5 (dimethicone 20 cSt) Total 100 100 100 100 100 100 100 100 PSA-4102:PSA-4302 100:0 87.5:12.5 75:25 50:50 25:75 12.5:87.5 0:100 0:100 Loss tangent (tan δ) 0.50 0.59 0.68 0.90 1.26 1.50 1.48 1.78 Viscosity (Pa .Math. s) — — — 26820 10072 5688 3161 — Cold flow area 2.79 1.06 1.64 2.80 4.82 10.08 36.50 74.00 ratio (%) Content relative to 96.81 91.11 82.68 82.91 84.1 81.77 80.5 75.54 initial content (%) 60° C. 2 W Probe tack value (gf) — 116 201 333 515 528 — — PSA-4102: BIO-PSA ® 7-4102 Silicone Adhesive (Dow Corning Corp.) PSA-4302: BIO-PSA ® 7-4302 Silicone Adhesive (Dow Corning Corp.) Silicone oil (dimethicone 20 cSt): Q7-9120 Silicone Fluid ® 20 cSt (Dow Corning Corp.)

[0065] In the table, the loss tangent (tan δ), viscosity (Pa.Math.s) and cold flow area ratio (%) were measured or calculated using the methods described in Examples 2 to 4.

[0066] In the table, the content of asenapine relative to the initial content (content relative to initial content (%)) was calculated as follows.

<Calculation of the Content Relative to Initial Content (%)>

[0067] The prepared patches are individually packaged in an aluminum bag, and asenapine contents were measured at immediately after production and after storage at 60° C. for 2 weeks (60° C.2W), under the following measurement conditions using high performance liquid chromatography (HPLC).

[Measurement Conditions]

[0068] Column: ODS column
Mobile phase solution: Methanol/(0.01 mol/L sodium lauryl sulfate in 0.1% phosphate solution)=3/1
Detection wavelength: 230 nm

[0069] The content relative to initial content is calculated as follows.

[Content relative to initial content (%)]=[Asenapine content after storage at 60° C.2W]÷[Asenapine content immediately after production]×100

[0070] In the table, the probe tack value (gf) was measured as follows.

<Measurement of Probe Tack Value (Gf)>

[0071] Measurement was performed using a probe tack tester (Rigaku Kogyo Co., Ltd., product name “Probe tack tester with digital counter”). The probe tack test conditions are as follows.

[Probe tack test conditions]
Probe material: Stainless steel
Probe diameter: 5 mmφ
Contact time: 1 sec
Contact weight: 4.9 N/cm.sup.2
Peeling speed: 10 mm/sec

[0072] As shown in Table 7, it was confirmed that patches 18 to 20 had a low cold flow area ratio and cold flow of the pressure-sensitive adhesive layer was suppressed; however, the adhesiveness was low. In addition, it was confirmed that the patch 25 had a large cold flow area ratio, and cold flow of the pressure-sensitive adhesive layer could not be suppressed. In contrast, it was confirmed that in patches 21 to 24, cold flow of the pressure-sensitive adhesive layer was suppressed and the patches had more excellent adhesiveness.

Example 7. Examination of Drug Concentration

[0073] Patches 26 to 28 were prepared according to the composition shown in Table 8. The mass of the pressure-sensitive adhesive was 100 g/m.sup.2 (set value).

TABLE-US-00008 TABLE 8 Patch Component 26 27 28 Asenapine (free form) 2 7 10 Silicone PSA-4202 98 93 90 Total (%) 100 100 100 Loss tangent (tan δ) 0.85 0.94 0.97 Viscosity (Pa .Math. s) — 27665 16985 Cold flow area ratio (%) 1.06 1.64 2.80

[0074] In the table, the loss tangent (tan δ), viscosity (Pa.Math.s) and cold flow area ratio (%) were measured or calculated using the methods described in Examples 2 to 4.

[0075] As shown in Table 8, it was confirmed that even when the drug concentration was changed, the cold flow area ratio was lowered by setting the loss tangent (tan δ) within the predetermined range.

Example 8. Examination of the Mass of Pressure-Sensitive Adhesive

[0076] Patches 29 to 32 were prepared according to the composition shown in Table 9.

TABLE-US-00009 TABLE 9 Patch Component 29 30 31 32 Asenapine (free form) 3.2 3.2 3.2 3.2 Silicone PSA-4202 96.8 96.8 96.8 96.8 Total (%) 100 100 100 100 Mass of adhesive (g/m.sup.2) 30 130 150 200 Loss tangent (tan δ) 0.90 0.90 0.90 0.90 Cold flow area ratio (%) 0.29 2.59 2.66 3.34

[0077] In the table, the loss tangent (tan δ) and the cold flow area ratio (%) were measured or calculated using the methods described in Examples 2 and 4.

[0078] As shown in Table 9, it was confirmed that even when the mass of the pressure-sensitive adhesive was changed within the range of 30 to 200 g/m.sup.2, the cold flow area ratio was lowered by setting the loss tangent (tan δ) within the predetermined range.