KR20200046461A - Composition comprising non-crystalline rotigotine and manufacturing method thereof - Google Patents

Abstract

The present invention provides a rotigotine-containing composition having secured stability, a patch containing the composition, and a method for stabilizing rotigotine. Especially, the present invention provides: a rotigotine-containing patch which can secure stability while not affecting or desirably affecting the skin permeation rate of rotigotine in manufacturing a patch formulation; and a method for manufacturing the rotigotine-containing patch.

Description

Composition comprising non-crystalline rotigotine and manufacturing method thereof

The present invention relates to compositions stably comprising amorphous rotigotine, patches comprising such compositions, and methods of making such compositions.

Rotigotine is known to be useful for the treatment of Parkinson's disease, Parkinson's plus syndrome, depression and restless leg syndrome, as well as for the treatment or prevention of dopamine neuronal loss. It is known that such rotigotine-containing medicines can be administered in a transdermal therapeutic system (TTS), patch, depot form, and the like.

Specifically, WO 94/07468 is essentially a continuous phase formed by a hydrophobic polymeric material, dispersing the hydrophilic phase contained therein, and active in a two-phase matrix mainly comprising drugs and hydrated silica. TTS comprising rotigotine hydrochloride as a material is disclosed. The silica is said to increase the maximum possible loading of TTS together with the hydrophilic salt. In addition, the formulation of WO 94/07468 mainly contains additional hydrophobic solvents, permeation promoting substances, dispersing agents and, in particular, emulsifiers necessary to emulsify aqueous solutions of the active ingredient on lipophilic polymers. do. However, this system did not provide satisfactory drug plasma concentrations.

On the other hand, WO 99/49852 discloses a TTS comprising an inert backing layer, a self-adhesive matrix layer comprising an effective amount of rotigotine or rotigotine hydrochloride and a protective film that is removed prior to use. . The matrix system consists of a non-aqueous polymer adhesion system based on acrylate or silicone.

On the other hand, such rotigotine may exist in various forms such as crystalline polymorph Form I, Form II, and is known to be very unstable, such as crystal polymorph changes in the composition and precipitation as crystals.

International patent application publication number WO 94/07468 International patent application publication number WO 99/49852 International patent application publication number WO 2011/076879

Therefore, the problem to be solved by the present invention is to provide a rotigotine-containing composition having stability, a patch containing the composition and a method for stabilizing rotigotine.

In particular, it is to provide a rotigotine-containing patch capable of securing the above-described stability and a method of manufacturing the same, while not affecting or desirably affecting the skin permeation rate of rotigotine in manufacturing the patch formulation.

In order to solve the above problems, the present invention provides a solid dispersion containing rotigotine, comprising a mixture of rotigotine and vinylpyrrolidone-vinyl acetate copolymer as an internal phase on the outer side of a silicone adhesive.

The present invention also disperses a mixed solution of rotigotine and vinylpyrrolidone-vinyl acetate copolymer forming an internal phase in a silicone-based adhesive solution forming an external phase, and then drying it (preferably, relatively low Provided is a method for stabilizing rotigotine in a silicone-based pressure sensitive adhesive, including drying at a temperature, for example, 90 ° C to 100 ° C.

In the case of International Patent Application Publication No. WO 2011/076879, it was intended to provide a composition and patch formulation having improved stability of rotigotine using polyvinylpyrrolidone. However, when using polyvinylpyrrolidone, the drying temperature must be increased in order to secure stability. In this case, there is a concern that rotigotine decomposes to generate a lot of related substances, and in particular, to maintain mixing uniformity in the dispersion. It is difficult, and there is a fear of layer separation.

In contrast, when the vinylpyrrolidone-vinyl acetate copolymer of the present invention is used as a solubilizing agent for improving stability, in particular, preventing crystallization, first, it is easy to secure mixing uniformity of the final dispersion before drying, and finally After the dispersion is prepared, rotigotine stability in the dispersion is excellent (mixing stability and stability against related substances), and layer separation does not occur, so it can be used for patch production for a longer time. Second, even when the drying temperature is low, it is possible to manufacture a composition and a patch having excellent stability, thereby suppressing the generation of a flexible substance that may occur when drying at a high temperature, and preventing the softening phenomenon of a film used for manufacturing the patch You can. In addition, thirdly, in the case of a patch manufactured by satisfying the above conditions, it exhibits very excellent stability.

As such a vinylpyrrolidone-vinyl acetate copolymer, a copolymer suitable for the specifications listed as copovidone in USP-NF, PhEur, or BP procedures can be used, for example, Kolidone® (BASF) VA64 Fine, Plasdone® S630, etc. Can be used.

In the present invention, as the rotigotine, a rotigotine free base or a pharmaceutically acceptable salt thereof may be used, and for example, acidic salts such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid may be used.

Preferably, in the present invention, the mixed weight ratio of rotigotine and vinylpyrrolidone-vinyl acetate copolymer contained in the dispersion is 9: 6 to 9:12 (rotigotine: vinylpyrrolidone-vinyl acetate copolymer). , More preferably, the mixing weight ratio is 9: 8 to 9:12. When the weight ratio of rotigotine to vinylpyrrolidone-vinyl acetate copolymer is about 9: 8 or more, a dried product having stability maintained regardless of the drying temperature can be prepared, and rotigotine to vinylpyrrolidone-vinyl acetate copolymer When the weight ratio of is less than about 9: 6 to 9: 8, the drying temperature is preferably 90 to 100 ° C from the viewpoint of securing stability. When a salt of rotigotine is used, the weight ratio is calculated based on the weight (i.e., reduced) in terms of rotigotine free base.

As will be described later, when the content of the copolymer is too high, it may be difficult to control the release of rotigotine, and when the content is too low, the drying temperature must be increased to increase stability related to crystal precipitation, and the rotigotine itself is raised due to the increased drying temperature. There is a risk of decomposition and generation of related substances. The vinylpyrrolidone-vinyl acetate copolymer of the present invention has an advantage that stability is maintained even at a low drying temperature.

In the solid dry dispersion of the present invention, as the silicone-based pressure-sensitive adhesive forming the external phase, preferably, an amine-compatible silicone pressure-sensitive adhesive may be used. For example, as a silicone adhesive, DOW CORNING's BIO-PSA ^TM 7-4101, 7-4201, 7-4301, 7-4102, 7-4202, 7-4302, 7-4103, 7-4203, 7-4303 , 7-4401, 7-4501, 7-4601, 7-4402, 7-4502, 7-4602, 7-4403, 7-4503, 7-4603, or mixtures thereof, more preferably, The silicone adhesive is BIO-PSA 7-4301, 7-4302, 7-4303, 7-4201, 7-4202, 7-4203, 7-4101, 7-4102, 7-4103 or mixtures thereof.

The solid dry dispersion of the present invention may optionally further include an antioxidant. As the antioxidant, sodium metabisulfite, ascorbyl palmitate, DL-alpha-tocopherol, totocophero acetate, butylated hydroxyanisole (BHA), butylated hydroxytoluene, propyl gallate, or a mixture thereof may be used. Preferably, as an antioxidant according to the present invention, sodium metabisulfite, ascorbyl palmitate, DL-alpha-tocopherol, or a mixture thereof is used.

Antioxidants according to the invention are included in the internal phase, for example, From the time of preparing the preparation (dispersion), the antioxidant can be administered by dissolving it in an appropriate solvent and then adding it. For example, sodium metabisulfite is prepared as a 10% aqueous solution, ascorbyl palmitate, and DL-alpha-tocopherol as a 10% ethanol solution, added to the formulation, and mixed into the internal phase.

As mentioned above, the present invention also includes dispersing a mixed solution of rotigotine and vinylpyrrolidone-vinyl acetate copolymer forming an internal phase in a silicone-based adhesive solution forming an external phase, and then drying it. To provide a method for stabilizing rotigotine in a silicone adhesive.

In this method, the weight ratio of rotigotine and vinylpyrrolidone-vinyl acetate copolymer, silicone-based adhesive, etc. are as mentioned above.

In the method according to the present invention, when an antioxidant is mixed, the internal phase is first mixed and the internal phase in which the antioxidant is mixed is mixed with the external phase to form a dispersion.

In the above method of the present invention, the drying temperature is 90 to 120 ° C, preferably 90 to 100 ° C. In the case of rotigotine, there is a possibility that a related substance may be generated when treated at a temperature exceeding 100 ° C, but the present invention can produce a patch composition having stability even when dried at a low temperature of 90 to 100 ° C. In particular, it is necessary to reduce the content of the vinylpyrrolidone-vinyl acetate copolymer in various aspects such as insufficient release of the drug. In the present invention, the mixed weight ratio of rotigotine and vinylpyrrolidone-vinyl acetate copolymer is 9: 6 to Even when a low amount of 9: 7 is used, it is possible to prepare a composition for patch excellent in stability in which crystals are not produced even when dried at a low temperature of 90 to 100 ° C.

When the mixed weight ratio of rotigotine and vinylpyrrolidone-vinyl acetate copolymer is 9: 6 to 9: 7, the drying temperature is preferably 90 to 100 ° C.

In the above method of the present invention, the silicone-based pressure-sensitive adhesive solution forming the external phase can be prepared using heptane, ethyl acetate, toluene or a mixture thereof, and the mixed solution containing rotigotine and copolymer forming the internal phase is ethanol, It can be prepared using ethyl acetate, toluene, or a mixed solvent thereof.

The present invention also provides a rotigotine patch comprising the solid dispersion. These rotigotine patches include a backing layer inert to the components of the matrix; A self-adhesive matrix layer (corresponding to the solid dispersion) comprising an effective amount of rotigotine or a pharmaceutically acceptable salt; And a protective layer that is removed prior to use.

The self-adhesive matrix layer may further include an antioxidant.

As the backing layer and the release liner, materials commonly used for patching may be used. For example, the backing layer may be made of polyurethane as well as polyolefin, especially polyethylene, or polyester. Also, preferably, a polyester foil such as a polyethylene terephthalate film can be used. The backing layer may include a thin aluminum layer.

The protective layer is a pull-off layer that is removed immediately before use, for example, polyurethane, polyvinyl acetate, polyvinylidene chloride, polypropylene, polycarbonate, polystyrene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, etc. Alternatively, paper coated with a corresponding polymer may be used. Preferably, a one-sided siliconized polymer foil is used as the protective layer.

The present invention provides a rotigotine-containing composition having a suitable transdermal permeability and a patch containing such a composition, in which stability of rotigotine is secured in a patch composition, particularly a composition containing a silicone-based adhesive. The present invention also provides a method for preparing a composition for transdermal administration that can secure rotigotine stability in a composition containing a silicone-based adhesive and exhibit proper transdermal permeability.

Particularly, in the case of rotigotine, there is a possibility that a related substance may be generated when treated at a temperature exceeding 100 ° C. The mixed weight ratio of rotigotine and vinylpyrrolidone-vinyl acetate copolymer is a low usage amount of 9: 6 to 9: 7. Even when it is used, even when dried at a low temperature of 90 to 100 ° C, it is possible to prepare a composition for patch excellent in stability in which crystals are not produced.

1 is a commercially available Neupro ^TM patch (2 mg), the results of the transdermal penetration test of Example 3 and Example 9. This is the result of percutaneous permeation experiment using EVA 9715 membrane instead of skin.
Figure 2 shows the results of a commercially available Neupro ^TM patch (2 mg) and percutaneous permeation experiments of some embodiments. It was evaluated using Hairless mouse skin.

Hereinafter, examples and the like will be described in detail to help understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more fully explain the present invention to those having average knowledge in the field to which the present invention pertains.

Preparation of Comparative Examples 1 to 12

A two-phase system was prepared having an external phase consisting of a self-adhesive polysiloxane polymer and an internal phase consisting of a polyvinylpyrrolidone / drug mixture. In the preparation solution, the self-adhesive polysiloxane adhesive on the outside is present as n-heptane, ethyl acetate, or a mixed solution thereof. Dow-Corning's BIO-PSA 7-4301 (n-heptane) or BIO-PSA 7-4302 (ethyl acetate) or a mixture thereof was used as an external phase, sodium metabisulfite (0.0006 wt%), ascobyl palmitate (0.02) as an antioxidant Weight percent), or DL-alpha-tocopherol (0.05 weight percent). The mixture constituting the internal phase was prepared by dissolving an amount selected from 2 to 12% by weight of polyvinyl acetate relative to 9% by weight of rotigotine at a suitable temperature in a 2: 5 mixed solution of ethanol and ethyl acetate (14% by weight). The outer phase and the inner phase were mixed at room temperature to form a homogeneous dispersion. After applying the prepared two-phase system, a patch was prepared by drying at various temperature conditions (60 ° C, 80 ° C, 90 ° C, 100 ° C, 120 ° C).

Sample No. Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Rotigotine 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight Polyvinylpyrrolidone Kollidone® K-90 F 2% by weight 4 wt% 6 wt% 8 wt% 10 wt% 12% by weight Ethanol / ethyl acetate (2: 5 w / w) 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight BIO-PSA 7-4301 (heptane) 7-430189% by weight 7-4301
87% by weight 7-4301
85% by weight 7-4301
83% by weight 7-4301
81% by weight 7-4301
79% by weight Remark Heptane solvent was used, and the drying temperature was varied for each comparative example to perform 5 conditions.

Sample No. Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Comparative Example 12 Rotigotine 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight Polyvinylpyrrolidone Kollidone® K-90 F 2% by weight 4 wt% 6 wt% 8 wt% 10 wt% 12% by weight Ethanol / ethyl acetate (2: 5 w / w) 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight BIO-PSA 7-4201 (ethyl acetate) 7-420189% by weight 7-4201
87% by weight 7-4201
85% by weight 7-4201
83% by weight 7-4201
81% by weight 7-4201
79% by weight Remark Ethyl acetate solvent was used, and the drying temperature was varied for each comparative example to perform 5 conditions.

Preparation of Examples 1-12

A two-phase system was prepared having an external phase consisting of a self-adhesive polysiloxane polymer and an internal phase consisting of a copovidone / drug mixture. In the preparation solution, the self-adhesive polysiloxane adhesive on the outside is present as n-heptane, ethyl acetate, or a mixed solution thereof. Dow-Corning's BIO-PSA 7-4301 (n-heptane) to BIO-PSA 7-4302 (ethyl acetate) was used as an external phase, and sodium metabisulfite, ascobyl palmitate, or DL-alpha-tocopherol was added as an antioxidant ( It was used in the same amount as in Comparative Examples 1 to 12). The mixture constituting the internal phase was prepared by dissolving an amount selected from 2 to 12% by weight of copovidone relative to 9% by weight of rotigotine at a suitable temperature in a 2: 5 mixed solution of ethanol and ethyl acetate (14% by weight). The outer phase and the inner phase were mixed at room temperature to form a homogeneous dispersion. After applying the prepared two-phase system, a patch was prepared by drying at various temperature conditions (60 ° C, 80 ° C, 90 ° C, 100 ° C, 120 ° C).

Sample No. Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Rotigotine 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight Copovidone Kollidone® VA64 Fine 2% by weight 4 wt% 6 wt% 8 wt% 10 wt% 12% by weight Ethanol / ethyl acetate (2: 5 w / w) 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight BIO-PSA 7-4301 (heptane) 7-430189% by weight 7-4301
87% by weight 7-4301
85% by weight 7-4301
83% by weight 7-4301
81% by weight 7-4301
79% by weight Remark Heptane solvent was used, and the drying temperature was varied for each Example to perform 5 conditions.

Sample No. Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Rotigotine 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight Copovidone Kollidone® VA64 Fine 2% by weight 4 wt% 6 wt% 8 wt% 10 wt% 12% by weight Ethanol / ethyl acetate (2: 5 w / w) 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight BIO-PSA 7-4201 (ethyl acetate) 7-420189% by weight 7-4201
87% by weight 7-4201
85% by weight 7-4201
83% by weight 7-4201
81% by weight 7-4201
79% by weight Remark Ethyl acetate solvent was used, and the drying temperature was varied for each example to perform 5 conditions.

Stability evaluation of raw solutions (preparation solutions)

In Comparative Examples 1 to 12, when the mixed stock solution was left at room temperature for 24 hours, between the outer phase (adhesive layer) made of a self-adhesive polysiloxane polymer and the inner phase made of polyvinylpyrrolidone / pharmaceutical complex (drug layer) Although phase separation occurred, in Examples 1 to 12, phase separation did not occur between the pressure-sensitive adhesive layer and the drug layer even if left at room temperature for 24 hours. Phase separation of the transdermal composition is an important factor that can have a decisive effect on the content and stability of the drug, and Examples 1 to 12 showed excellent stock solution stability without phase separation between the adhesive layer and the drug layer even if left at room temperature for a long time. In addition, as a result of confirming each of the prepared stock solutions by a related material analysis method, Examples 1 to 12 showed better superior stock solution stability compared to Comparative Examples 1 to 12 because the initial related materials were hardly detected.

Patch stability evaluation

Acceleration, harshness, and long-term stability tests were performed on a number of patches of the same conditions prepared in Comparative Examples 1 to 12 and Examples 1 to 12. Examples 1 to 12 showed better patch stability results when compared to Comparative Examples 1 to 12.

Related substances analysis

Column: Gemini C18 (50 × 4.6mm, 3um)

Elution

Time (minutes) Mobile phase A
(% v / v) Mobile phase B
(% v / v) Remark 0-15 80 → 50 20 → 50 Gradient 15-22 50 → 20 50 → 80 Gradient 22-27 20 80 Isocratic 27-28 20 → 80 80 → 20 Return to initial conditions 28-31 Post-time: 3 min Re-equilibrate

Flow: 1.8ml / min

Oven temperature: 40 ℃

DAD wavelength: 215nm

Injection volume: 5 μl

Solution A: pH 9.5 10mM ammonium bicarbonate solution

Solution B: Acetonitrile

Patch crystal stability

It is a result of observing changes in properties during 2 months to 2 months storage under accelerated and severe conditions (alu-pouch storage).

Long-term condition: 25 ℃, 60% RH

Acceleration condition: 40 ℃, 75% RH

Severe conditions: 60 ℃

The results of the two-month stability evaluation under harsh conditions are shown in Table 6 below.

Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Drying temperature 60 ℃ Detected Detected Detected Detected N / D N / D Drying temperature 80 ℃ Detected Detected Detected Detected N / D N / D Drying temperature 90 ℃ Detected Detected Detected Detected N / D N / D Drying temperature 100 ℃ Detected Detected Detected Detected N / D N / D Drying temperature 120 ℃ Detected Detected N / D N / D N / D N / D Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Drying temperature 60 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 80 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 90 ℃ Detected Detected N / D N / D N / D N / D Drying temperature 100 ℃ Detected Detected N / D N / D N / D N / D Drying temperature 120 ℃ Detected Detected N / D N / D N / D N / D

In Tables 6 to 10, "Detected" means that crystal precipitation was observed inside the patch, and "N / D (Not Detected)" indicates that crystals were not precipitated inside the patch and were stable.

The accelerated condition 3-month stability evaluation results are shown in Table 7 below.

Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Drying temperature 60 ℃ Detected Detected Detected Detected N / D N / D Drying temperature 80 ℃ Detected Detected Detected Detected N / D N / D Drying temperature 90 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 100 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 120 ℃ Detected Detected N / D N / D N / D N / D Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Drying temperature 60 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 80 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 90 ℃ Detected Detected N / D N / D N / D N / D Drying temperature 100 ℃ Detected Detected N / D N / D N / D N / D Drying temperature 120 ℃ Detected Detected N / D N / D N / D N / D

Long-term conditions 3 months stability evaluation results are shown in Table 8 below.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Drying temperature 60 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 80 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 90 degrees Detected Detected N / D N / D N / D N / D Drying temperature 100 ℃ Detected Detected N / D N / D N / D N / D Drying temperature 120 ℃ Detected Detected N / D N / D N / D N / D

The accelerated condition 6-month stability results, the harsh condition 6-month stability results, and the long-term condition stability results of Examples according to the present invention are shown in Tables 9 to 11, respectively.

6 months accelerated Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Drying temperature 60 ℃ Detected Detected Detected Detected N / D N / D Drying temperature 80 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 90 degrees Detected Detected N / D N / D N / D N / D Drying temperature 100 ℃ Detected Detected N / D N / D N / D N / D Drying temperature 120 ℃ Detected Detected N / D N / D N / D N / D

Harsh 6 months Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Drying temperature 60 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 80 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 90 degrees Detected Detected N / D N / D N / D N / D Drying temperature 100 ℃ Detected Detected N / D N / D N / D N / D Drying temperature 120 ℃ Detected Detected N / D N / D N / D N / D

Long term 12 months Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Drying temperature 60 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 80 ℃ Detected Detected Detected N / D N / D N / D Drying temperature 90 degrees Detected Detected N / D N / D N / D N / D Drying temperature 100 ℃ Detected Detected N / D N / D N / D N / D Drying temperature 120 ℃ Detected Detected N / D N / D N / D N / D

From the evaluation results, it was confirmed that the example using copovidone as a stabilizer showed a much better result in terms of crystal stability in the patch compared to the comparative example using polyvinylpyrrolidone. Particularly, in the case of long-term storage for harshness and acceleration, in the comparative example, when the ratio of rotigotine and polyvinylpyrrolidone was 9: 6 (weight ratio), crystals were generated in the sample performed at a drying temperature of 100 ° C, and the drying temperature was 90 under accelerated conditions Although crystals were generated in the sample at ℃, no crystal generation was observed when copovidone was used. In addition, since the occurrence of crystals was not observed even in storage for a long period of 12 months or longer, excellent results were confirmed compared to the existing ones.

In addition, from these results, it is possible to manufacture a patch having excellent crystal stability when the drying temperature for preparing the patch is 90 ° C or more and 100 ° C or less, while copovidone is contained in an amount of 6 parts by weight or more compared to 9 parts by weight of rotigotine. I could confirm.

Evaluation of patch transdermal permeability

Percutaneous transmittance experiments were performed using the patches prepared in the previous examples or commercially available Neupro® patches. The experimental conditions were as follows.

Franz Diffusion Cell Experimental Parameters

Apparatus: Hansen Automated Franz diffusion cell sampling system

Cell volume: 7.0 mL

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

Test formulations: Examples 3 and 9 (Comparative Example: Neupro® patch)

Dose: 0.45 mg over a 1.0 cm ² area as rotigotine base; occluded

Duration: 72 hours

Temperature: 32.5 ℃

Sample volume: 0.9 mL

Rinse volume: 1.6 mL

Sample analysis: HPLC

Membrane: 3M EVA 9715 membrane

The results are shown in Table 12, FIGS. 1 and 2.

Average Amount
Penetration at 24 hours (μg / cm ² ) Average Amount
Penetrating at 36 hours (μg / cm ² ) Comparative Example (Neupro® patch) 304.2 322.4 Example 3 (when the polysiloxane adhesive is n-heptane) 295.5 322.0 Example 9 (When the polysiloxane adhesive is ethyl acetate) 330.0 348.1

From the results of Table 12 and the results of FIGS. 1 and 2, it can be seen that the embodiments of the present invention not only greatly improved the stock solution stability and patch stability, but also showed equivalent transdermal permeability to Neupro® Patch.

Claims (12)

A rotigotine-containing solid dispersion comprising a mixture of rotigotine and vinylpyrrolidone-vinyl acetate copolymer on the outer phase of a silicone adhesive. The solid dispersion according to claim 1, wherein the mixed weight ratio of the rotigotine and the vinylpyrrolidone-vinyl acetate copolymer is 9: 6 to 9:12 (rotigotine: copolymer). The solid dispersion according to claim 1, wherein the silicone-based adhesive is an amine-compatible silicone adhesive. The solid dispersion of claim 1, wherein the dispersion further comprises an antioxidant. A rotigotine patch comprising the solid dispersion of claim 1. After dispersing a mixed solution of rotigotine and vinylpyrrolidone-vinyl acetate copolymer forming an internal phase in a silicone-based adhesive solution forming an external phase, stabilizing the rotigotine in a silicone-based adhesive comprising drying it. How to. The method of claim 6, wherein the drying is performed at 90 ° C to 120 ° C. The method of claim 7, wherein the drying is performed at 90 ° C to 100 ° C. The method of claim 6, wherein the mixed weight ratio of the rotigotine and vinylpyrrolidone-vinyl acetate copolymer is 9: 6 to 9:12 (rotigotine: copolymer). The method of claim 6, wherein the silicone-based adhesive is an amine-compatible silicone adhesive. The method of claim 6, wherein an antioxidant is further included in the dispersion. A rotigotine patch comprising a solid dispersion prepared by the method of claim 6.

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