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 hydrophobic silica.

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/cm.sup.2 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 hydrophobic silica is a hydrophobic fumed silica.

5. The rivastigmine patch of claim 1, wherein the content of the hydrophobic silica is 10-50% by weight based on the total weight of the rivastigmine matrix layer.

6. The rivastigmine patch of claim 5, wherein the rivastigmine matrix layer comprises 10-50% by weight of rivastigmine, 5-30% by weight of hydrophobic silica, and 30-80% by weight of an acrylic adhesive based on the total weight of the rivastigmine matrix layer.

7. The rivastigmine patch of claim 6, wherein the acrylic adhesive is a random copolymer of 58-66 parts by weight of 2-ethylhexyl acrylate, 28-36 parts by weight of methyl acrylate, and 4-8 parts by weight of acrylic acid.

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

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

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

11. The rivastigmine patch of claim 10, wherein the self-adhesive matrix layer comprises a mixture of BIO-PSA 7-4201 and 7-4301.

12. The rivastigmine patch of claim 11, wherein the self-adhesive matrix layer comprises a 1:1 weight ratio mixture of BIO-PSA 7-4201 and 7-4301.

13. The rivastigmine patch of claim 5, 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.

14. The rivastigmine patch of claim 5, 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.

15. The rivastigmine patch of claim 5, wherein the hydrophobic silica is a hydrophobic fumed silica.

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.

[0044] FIGS. 4 to 6 are graphs showing changes in cumulative permeation amount (mg/cm.sup.2), cumulative permeation percentage (%), and permeation rate (μg/cm.sup.2/hour), respectively, of examples for evaluating the effect of a change in content.

MODE FOR INVENTION

[0045] 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.

[0046] In the following comparative examples and examples, when expressed as simply “%” it means % by weight.

[0047] 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.

[0048] 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

[0049] 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

[0050] 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

[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% aerosil (AEROSIL® R 972 Pharma), 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

[0052] A patch with a triple layer system consisting of (1) a backing film, (2) a self-adhesive matrix layer consisting of 30% rivastigmine, 15% aerosil (AEROSIL® R 972 Pharma), 0.1% DL-alpha-tocopherol, 5% Plastoid B, and 49.9% self-adhesive acrylic adhesive, (3) a release-controlling membrane, (4) a self-adhesive matrix layer consisting of a self-adhesive polysiloxane polymer 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

[0053] A patch with a triple layer system consisting of (1) a backing film, (2) a self-adhesive matrix layer consisting of 30% rivastigmine, 15% aerosil (AEROSIL® R 972 Pharma), 0.1% DL-alpha-tocopherol, 5% Eudragit L100, and 49.9% self-adhesive acrylic adhesive, (3) a release-controlling membrane, (4) a self-adhesive matrix layer consisting of a self-adhesive polysiloxane polymer 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 0.42% 0.29% 0.38% Example 2 0.41% 0.38% 0.39% Example 3 0.61% 0.40% 0.57%

[0068] As shown in Table 1, the rivastigmine patch according to the present invention maintained its stability even if it contained a high amount of rivastigmine. When Eudragit L100 was additionally comprised in the rivastigmine matrix layer, the stability of rivastigmine was relatively inferior.

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 Cold flow Shear Tack (g) (creep & heat test) Comparative Desorption within >200 g Very severe example 1 24 hours Comparative Desorption within >200 g Very severe example 2 1 hour Example 1 72 hours or more 100~150 g Almost none Example 2 72 hours or more 100~150 g Almost none Example 3 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 5 and FIGS. 1 to 2.

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

TABLE-US-00004 TABLE 4 Day Exelon ® patch Example 1 Example 2 Example 3 0 0.0 0.0 0.0 0.0 1 53.6 12.8 11.0 12.0 2 68.9 21.1 17.0 19.0 3 70.6 28.0 23.0 25.0 4 72.9 35.3 28.0 31.0 7 76.0 51.4 37.0 42.0 Content 1.80 5.68 5.52 5.46 (mg/cm.sup.2)

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

TABLE-US-00005 TABLE 5 Day Exelon ® patch Example 1 Example 2 Example 3 1 965 725 620 630 2 1239 1198 940 980 3 1271 1592 1260 1300 4 1312 2007 1540 1590 7 1367 2919 2040 2310 Content 1.80 5.68 5.52 5.46 (mg/cm2)

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

TABLE-US-00006 TABLE 6 Day Exelon ® patch Example 1 Example 2 Example 3 0.5 40.2 30.2 25.9 26.3 1.5 11.4 19.7 13.3 14.4 2.5 1.3 16.4 13.4 13.5 3.5 1.7 17.3 — — 4.5 — — — — 5.0 — —  8.1  8.9 5.5 0.8 12.7 — — Content 1.80  5.68  5.52  5.46 (mg/cm2)

[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.

Experimental Example 4 (Evaluation of the Effect of Different Types of Silica

[0091] Rivastigmine patches were prepared in the same manner as in Example 1, except that the components and contents of the rivastigmine matrix layer were prepared as shown in Table 7 below, and evaluated in substantially the same manner as in the experimental examples. The results are summarized and shown in Table 7 below.

TABLE-US-00007 TABLE 7 API Content Shear Sample No. Characteristics (mg/cm.sup.2) Probe Tack Release peel (200 g, 5 cm.sup.2) Example a 50% rivastigmine, 10.0 160.0 ± 22.8 Excellent Inadequate 12% Aerosil A200P, Residual quantity of DT 235A Example b 44% rivastigmine, 8.9 63.4 ± 7.2 Excellent N/A 22% Aerosil A200P, Residual quantity of DT 235A Example c 50% rivastigmine, 9.3 154.2 ± 23.2 Excellent Excellent 12% Aerosil A200P, Residual quantity of DT 235A Example d 44% rivastigmine, It was impossible to prepare. 22% Aerosil A200P, Residual quantity of DT 235A Example e 50% rivastigmine, 10.0 131.5 ± 11.2 Inadequate Excellent 12% Aerosil A300P, Residual quantity of DT 235A Example f 44% rivastigmine, 8.9 35.4 ± 4.6 Inadequate N/A 22% Aerosil A300P, Residual quantity of DT 235A Example g 50% rivastigmine, 10.5 120.9 ± 27.3 B/F and membrane Inadequate 12% Aeroperl 300P, separation Residual quantity of DT phenomenon occurs 235A Example h 44% rivastigmine, — Cohesion Failure It was difficult N/A 22% Aeroperl 300P, to prepare. Residual quantity of DT 235A Example i 44% rivastigmine, 9.5 150.2 ± 19.4 Release Peel Excellent 22% Aerosil R972P, Excellent (kept >24 h) Residual quantity of DT 235A

[0092] In Table 7, A200P means A 200 Pharma, A300P means A 300 Pharma, Aeroperl 300P means 300 Pharma, and R972P means R 972 Pharma. In Table 7, B/F means a backing film.

[0093] As shown in Table 7, when using Aerosil A200 and A300, the tap density was low, the properties were floppy, and it was difficult to use, and there was a problem in preparing the compositions for preparation of the patch. In the case of Aeroperl 300, it is easy to use because it has good solid properties, but when the amount is small, the tack improvement effect is small and cold flow is also severe. When the amount was increased, tack disappeared at all, and cohesion failure occurred at the level of loss of adhesion. In the case of Aerosil R972, it was easy to use due to its good solid properties. When using hydrophilic fumed silica, it is difficult to manufacture or product quality problems such as cold flow occurred.

Experimental Example 5 (Evaluation According to Rivastigmine Content

[0094] According to Table 8 below, rivastigmine patches were prepared in a similar manner to Example 1. The following samples were prepared at 180 GSM based on the drug layer.

TABLE-US-00008 TABLE 8 796-169- 796-169- 796-169- 796-169- 796-169- 796-169- 796-169- Item DT235A- DT235A- DT235A- DT235A- DT235A- DT235A- DT235A- (Unit: wt %) RVS10 RVS15 RVS20 RVS25 RVS30 RVS35 RVS40 Rivastigmine Rivastigmine 10% 15% 20% 25% 30% 35% 40% matrix layer (Content of 1.8 2.7 3.6 4.5 5.4 6.3 7.2 rivastigmine mg/cm.sup.2 mg/cm.sup.2 mg/cm.sup.2 mg/cm.sup.2 mg/cm.sup.2 mg/cm.sup.2 mg/cm.sup.2 per unit area mg/cm.sup.2) R972 20% 20% 20% 20% 20% 20% 20% DT235A 70% 65% 60% 55% 50% 45% 40% (solids 40%) DL-Alpha- 0.1%  0.1%  0.1%  0.1%  0.1%  0.1%  0.1%  Tocopherol Release controlling 3M Cotran 9707 membrane Self-adhesive BIO-PSA 7- 99.9% matrix layer 4201 DL-Alpha- 0.1% Tocopherol

[0095] Thereafter, similar to Experimental Example 3, the transdermal permeation rate was measured for 7 days, and the results are shown in FIGS. 4 to 6. As shown in FIGS. 4 to 6, the rivastigmine patches according to the present invention could maintain a constant flux to some extent even after time.

Experimental Example 6 (Evaluation of Chemical Stability of Rivastigmine

[0096] According to Table 9 below, rivastigmine patches were prepared in a similar manner to Example 1. The following samples were prepared at 180 GSM based on the drug layer.

TABLE-US-00009 TABLE 9 796-185-SK Item 796-185-SK (No R972) Rivastigmine Rivastigmine 40% 40% matrix (Content of rivastigmine 7.2 mg/cm.sup.2 7.2 mg/cm.sup.2 layer per unit area mg/cm.sup.2) R972 20%  0% DT235A (solids 40%) 40% 60% DL-Alpha-Tocopherol 0.1%  0.1%  Release controlling 3M Cotran 9707 membrane Self- BIO-PSA 99.9% adhesive 7-4201 matrix DL-Alpha- 0.1% layer Tocopherol

[0097] The results of evaluating the degradation degree of rivastigmine after storing the samples prepared in Table 9 under severe conditions for 2 weeks are shown in Table 10 below.

TABLE-US-00010 TABLE 10 Patch (Accelerated condition, 60° C. 2 weeks) Single Max Total Purity Sample ID Impurity Impurities at Final 796-185_SK 0.24% 0.37% 99.63% 796-185_SK 1.20% 1.98% 98.02% (NO R972)

[0098] As shown in Table 10, when the hydrophobic silica is comprised according to the present invention, it was confirmed that the stability of rivastigmine was greatly helpful.