METHYLPHENIDATE-CONTAINING TRANSDERMAL PATCH

Abstract

The present invention addresses the problem of providing a methylphenidate-containing transdermal patch in which cold flow beyond the edge of the patch containing methylphenidate is inhibited, and which has sufficient physical properties as a preparation, and excellent handleability. The present invention pertains to: a transdermal patch comprising a backing layer and an adhesive layer, wherein the adhesive layer contains methylphenidate, a rubber-based adhesive agent, and an acrylic adhesive agent, and the mixing ratio of the rubber-based adhesive agent to the acrylic adhesive agent is 9:1 to 1:9, and a production method for the transdermal patch.

Claims

1. A patch comprising a backing layer and an adhesive layer, wherein the adhesive layer contains methylphenidate, a rubber-based adhesive and an acrylic-based adhesive, and the mixing ratio of the rubber-based adhesive and the acrylic-based adhesive is 9:1 to 1:9.

2. The patch according to claim 1, wherein the rubber-based adhesive contains a styrene-isoprene-styrene block copolymer.

3. The patch according to claim 1, wherein the rubber-based adhesive contains a tackifying resin.

4. The patch according to claim 1, wherein the acrylic-based adhesive does not have a carboxyl group.

5. The patch according to claim 1, wherein the rubber-based adhesive contains an alicyclic hydrocarbon resin and/or a terpene-based resin as a tackifying resin.

6. The patch according to claim 1, wherein the adhesive layer contains methylphenidate in a proportion of 10 to 30 mass % relative to the total amount of the adhesive layer.

7. The patch according to claim 1, wherein the mixing ratio of the rubber-based adhesive and the acrylic-based adhesive is 9:1 to 3:7.

8. The patch according to claim 5, wherein the mixing ratio of the alicyclic hydrocarbon resin and the terpene-based resin is 2:1 to 1:2.

Description

EXAMPLES

[0058] <Cold Flow Test>

[0059] [Experimental Method]

[0060] Methylphenidate-containing patches shown in Tables 1-1 to 1-8 were produced, then these patches were respectively put into packaging bags and stored at room temperature; after 10 months, cold flow of the preparation from four sides was visually observed. Cold flow scores were set as follows. [0061] 1: No cold flow [0062] 2: Very slight cold flow [0063] 3: Cold flow from less than one side [0064] 4: Cold flow from less than two sides [0065] 5: Cold flow from two sides or more [0066] 6: Cold flow from all sides

[0067] [Experimental Result]

[0068] The results of the cold flow test are shown in Tables 1-1 to 1-8. For all of the patches (Examples 1 to 35) containing the rubber-based adhesive and the acrylic-based adhesive in the mixing ratio of 9:1 to 1:9, the cold flow score was about 1 to 3, indicating excellent effect of suppressing cold flow. It was also shown that the cold flow score changed depending on which materials were used for the rubber-based adhesive and the acrylic-based adhesive in the patch; in particular, the cold flow score was 1 for those containing SIS in the rubber-based adhesive and alicyclic saturated hydrocarbon resin (ARKON) and/or a terpene-based resin (YS resin) in the tackifying resin (Examples 26 to 30), and for those containing SIS, alicyclic saturated hydrocarbon resin, and terpene-based resin in the rubber-based adhesive (Example 33, etc.), indicating excellent effect of suppressing cold flow.

[0069] Here, the degree of cold flow of the preparations after 10 months at room temperature was similar to that of the preparations stored at 60 C. for 1 week or at 40 C. for 1 to 3 months.

TABLE-US-00001 TABLE 1-1 Results of cold flow test (Comparative Examples) Com. Ex. Com. Ex. Component 1 2 Methylphenidate (mass %) 20 20 SIS (mass %) 29 0 Alicyclic saturated hydrocarbon 31 0 resin (mass %) Terpene-based resin (mass %) 20 0 MAS-811 (mass %) 0 80 Total (mass %) 100 Rubber-based adhesive: 10:0 0:10 Acrylic-based adhesive Cold flow score 4 6

TABLE-US-00002 TABLE 1-2 Results of cold flow test (Examples 1-5) Ex. Ex. Ex. Ex. Ex. Component 1 2 3 4 5 Methylphenidate (mass %) 20 20 20 20 20 SIS (mass %) 38.4 29.9 21.3 12.8 4.27 Alicyclic saturated 33.6 26.1 18.7 11.2 3.73 hydrocarbon resin (mass %) MAS-811 (mass %) 8 24 40 56 72 Total (mass %) 100 Rubber-based adhesive: 9:1 7:3 5:5 3:7 1:9 Acrylic-based adhesive Cold flow score 1 1 2 3 3

TABLE-US-00003 TABLE 1-3 Results of cold flow test (Examples 6-10) Ex. Ex. Ex. Ex. Ex. Component 6 7 8 9 10 Methylphenidate (mass %) 20 20 20 20 20 SIS (mass %) 38.4 29.9 21.3 12.8 4.27 Terpene-based resin (mass %) 33.6 26.1 18.7 11.2 3.73 MAS-811 (mass %) 8 24 40 56 72 Total (mass %) 100 Rubber-based adhesive: 9:1 7:3 5:5 3:7 1:9 Acrylic-based adhesive Cold flow score 1 1 2 2 3

TABLE-US-00004 TABLE 1-4 Results of cold flow test (Examples 11-15) Ex. Ex. Ex. Ex. Ex. Component 11 12 13 14 15 Methylphenidate (mass %) 20 20 20 20 20 SIS (mass %) 38.4 29.9 21.3 12.8 4.27 Alicyclic saturated 33.6 26.1 18.7 11.2 3.73 hydrocarbon resin (mass %) Duro-Tak87-4098 (mass %) 8 24 40 56 72 Total (mass %) 100 Rubber-based adhesive: 9:1 7:3 5:5 3:7 1:9 Acrylic-based adhesive Cold flow score 1 1 1 2 2

TABLE-US-00005 TABLE 1-5 Results of cold flow test (Examples 16-20) Ex. Ex. Ex. Ex. Ex. Component 16 17 18 19 20 Methylphenidate (mass %) 20 20 20 20 20 SIS (mass %) 38.4 29.9 21.3 12.8 4.27 Alicyclic saturated 33.6 26.1 18.7 11.2 3.73 hydrocarbon resin (mass %) Duro-Tak87-4287 (mass %) 8 24 40 56 72 Total (mass %) 100 Rubber-based adhesive: 9:1 7:3 5:5 3:7 1:9 Acrylic-based adhesive Cold flow score 1 1 1 2 2

TABLE-US-00006 TABLE 1-6 Results of cold flow test (Examples 21-25) Ex. Ex. Ex. Ex. Ex. Component 21 22 23 24 25 Methylphenidate (mass %) 20 20 20 20 20 SIS (mass %) 38.4 29.9 21.3 12.8 4.27 Terpene-based resin (mass %) 33.6 26.1 18.7 11.2 3.73 Duro-Tak87-4098 (mass %) 8 24 40 56 72 Total (mass %) 100 Rubber-based adhesive: 9:1 7:3 5:5 3:7 1:9 Acrylic-based adhesive Cold flow score 1 1 1 2 2

TABLE-US-00007 TABLE 1-7 Results of cold flow test (Examples 26-30) Ex. Ex. Ex. Ex. Ex. Component 26 27 28 29 30 Methylphenidate (mass %) 20 20 20 20 20 SIS (mass %) 38.4 29.9 21.3 12.8 4.27 Terpene-based resin (mass %) 33.6 26.1 18.7 11.2 3.73 Duro-Tak87-4287 (mass %) 8 24 40 56 72 Total (mass %) 100 Rubber-based adhesive: 9:1 7:3 5:5 3:7 1:9 Acrylic-based adhesive Cold flow score 1 1 1 1 1

TABLE-US-00008 TABLE 1-8 Results of cold flow test (Examples 31-35) Ex. Ex. Ex. Ex. Ex. Component 31 32 33 34 3 5 Methylphenidate (mass %) 20 20 20 20 20 SIS (mass %) 38.4 21.3 4.28 21.3 21.3 Alicyclic saturated 16.8 9.35 1.86 12.47 6.23 hydrocarbon resin (mass %) Terpene-based resin (mass %) 16.8 9.35 1.86 6.23 12.47 MAS-683 (mass %) 8 40 72 40 40 Total (mass %) 100 Rubber-based adhesive: 9:1 3:7 1:9 5:5 5:5 Acrylic-based adhesive Alicyclic saturated 1:1 1:1 1:1 2:1 1:2 hydrocarbon resin: Terpene-based resin Cold flow score 1 2 1 2 1

[0070] <Phase Separation Test 1>

[0071] [Experimental Method]

[0072] The phase separation of the preparations was visually observed at room temperature during or immediately after production of the patches of Examples 1 to 5 and 11 to 20 described above. The evaluation criteria were set as follows. For convenience, those with a rating of 80 or more were judged to have excellent production suitability. [0073] 100: No phase separation in appearance (uniform preparation) [0074] 80: Slight pattern of phase separation is observed [0075] 60: Pattern of phase separation is observed [0076] 40: Phase separation is remarkable [0077] 20: Separation at the time of application [0078] 0: Application impossible

[0079] [Experimental Result]

[0080] The results of the phase separation test are shown in Tables 2-1 to 2-3. The phase separation scores of all the patches of Examples 1 to 5, 11, 14, 16 to 20 were 80 or more.

[0081] While the preparations with an evaluation of 20 or more and less than 80 showed phase separation in appearance, permeability of the drug and adhesiveness of the preparations were about the same as the preparations without phase separation.

TABLE-US-00009 TABLE 2-1 Results of phase separation test (Examples 1-5) Ex. Ex. Ex. Ex. Ex. Component 1 2 3 4 5 Methylphenidate (mass %) 20 20 20 20 20 SIS (mass %) 38.4 29.9 21.3 12.8 4.27 Alicyclic saturated 33.6 26.1 18.7 11.2 3.73 hydrocarbon resin (mass %) MAS-811 (mass %) 8 24 40 56 72 Total (mass %) 100 Rubber-based adhesive: 9:1 7:3 5:5 3:7 1:9 Acrylic-based adhesive Phase separation score 90 85 85 85 90

TABLE-US-00010 TABLE 2-2 Results of phase separation test (Examples 11-15) Ex. Ex. Ex. Ex. Ex. Component 11 12 13 14 15 Methylphenidate (mass %) 20 20 20 20 20 SIS (mass %) 38.4 29.9 21.3 12.8 4.27 Alicyclic saturated 33.6 26.1 18.7 11.2 3.73 hydrocarbon resin (mass %) Duro-Tak87-4098 (mass %) 8 24 40 56 72 Total (mass %) 100 Rubber-based adhesive: 9:1 7:3 5:5 3:7 1:9 Acrylic-based adhesive Phase separation score 85 30 60 80 20

TABLE-US-00011 TABLE 2-3 Results of phase separation test (Examples 16-20) Ex. Ex. Ex. Ex. Ex. Component 16 17 18 19 20 Methylphenidate (mass %) 20 20 20 20 20 SIS (mass %) 38.4 29.9 21.3 12.8 4.27 Alicyclic saturated 33.6 26.1 18.7 11.2 3.73 hydrocarbon resin (mass %) Duro-Tak87-4287 (mass %) 8 24 40 56 72 Total (mass %) 100 Rubber-based adhesive: 9:1 7:3 5:5 3:7 1:9 Acrylic-based adhesive Phase separation score 90 85 80 85 90

[0082] <Phase Separation Test 2>

[0083] [Experimental Method]

[0084] The patches containing methylphenidate with the compositions shown in Tables 3-1 to 3-4 were produced as those wherein the rubber-based adhesive SIS (100 parts by weight) and the alicyclic saturated hydrocarbon resin (Alcon) (87.5 parts by weight) were mixed, then phase separation of these patches was evaluated in the same manner as in the phase separation test 1 above.

[0085] [Experimental Result]

[0086] The results of the phase separation test are shown in Tables 3-1 to 3-4. In contrast to the results of the above-mentioned phase separation test 1, all of the patches containing calcium silicate (Examples 36, 42-47) had a phase separation score of 100, indicating excellent effect of suppressing phase separation. Meanwhile, all of the patches without calcium silicate and containing methylphenidate and a rubber-based adhesive or an acrylic-based adhesive (Reference Examples 1 to 5) had a phase separation score of 100, so the phase separation was not recognized.

TABLE-US-00012 TABLE 3-1 Results of phase separation test (Reference Examples 1-5) Ref. Ex. Ref. Ex. Ref. Ex. Ref. Ex. Ref. Ex. Component 1 2 3 4 5 Methylphenidate(mass %) 20 20 20 20 20 Calcium silicate(mass %) 0 0 0 0 0 Rubber-based 80 0 0 0 0 adhesive (mass %) MAS-683 (mass %) 0 80 0 0 0 MAS-811 (mass %) 0 0 80 0 0 Duro-Tak87-4098(mass %) 0 0 0 80 0 Duro-Tak87-4287(mass %) 0 0 0 0 80 Total (mass %) 100 Rubber-based adhesive: 10:0 0:10 0:10 0:10 0 :10 Acrylic-based adhesive Phase separation score 100 100 100 100 100

TABLE-US-00013 TABLE 3-2 Results of phase separation test (Examples 36-41) Ex. Ex. Ex. Ex. Ex. Ex. Component 36 37 38 39 40 41 Methylphenidate (mass %) 20 20 20 20 20 20 Calcium silicate (mass %) 1 0 0 0 0 0 Rubber-based adhesive 39.5 72 56 40 24 8 (mass %) MAS-683 (mass %) 39.5 8 24 40 56 72 Total (mass %) 100 Rubber-based adhesive: 5:5 9:1 7:3 5:5 3:7 1:9 Acrylic-based adhesive Phase separation score 100 90 50 30 85 90

TABLE-US-00014 TABLE 3-3 Results of phase separation test (Examples 42-45) Ex. Ex. Ex. Ex. Component 42 43 44 45 Methylphenidate (mass %) 20 20 20 20 Calcium silicate (mass %) 0.1 1 2.5 5 Rubber-based adhesive (mass %) 39.95 39.5 38.75 37.5 MAS-811 (mass %) 39.95 39.5 38.75 37.5 Total (mass %) 100 Rubber-based adhesive: 5:5 5:5 5:5 5:5 Acrylic-based adhesive Phase separation score 100 100 100 100

TABLE-US-00015 TABLE 3-4 Results of phase separation test (Examples 46, 47) Ex. Ex. Component 46 47 Methylphenidate (mass %) 20 20 Calcium silicate (mass %) 1 1 Rubber-based adhesive (mass %) 39.5 39.5 Duro-Tak87-4098 (mass %) 39.5 0 Duro-Tak87-4287 (mass %) 0 39.5 Total (mass %) 100 Rubber-based adhesive: 5:5 5:5 Acrylic-based adhesive Phase separation score 100 100

[0087] <Phase Separation Test 3>

[0088] [Experimental Method]

[0089] Patch containing methylphenidate with the compositions shown in Table 4 were produced, then the phase separation of these patches was evaluated in the same manner as in the phase separation test 1 above.

[0090] [Experimental Result]

[0091] Table 4 shows the results of the phase separation test. Examples 48 and 49 correspond to those that contain calcium silicate in Examples 12 and 15, respectively. In both of Examples 48 and 49 containing calcium silicate, the phase separation score was 100, indicating an excellent effect of suppressing phase separation.

TABLE-US-00016 TABLE 4 Results of phase separation test (Examples 48, 49) Ex. Ex. Component 48 49 Methylphenidate (mass %) 20 20 Calcium silicate (mass %) 1 1 SIS (mass %) 29.5 4.22 Alicyclic hydrocarbon 29.5 3.68 resin (mass %) Duro-Tak87-4098 (mass %) 23.7 71.1 Total (mass %) 100 Rubber-based adhesive: 7:3 1:9 Acrylic-based adhesive Phase separation score 100 100