WO2024040860A1 - Rotigotine transdermal drug delivery system inhibiting crystallization, method for preparing same, and use thereof - Google Patents

Abstract

The present invention relates to a rotigotine transdermal drug delivery system inhibiting drug crystallization, a method for preparing same, and use thereof. Rotigotine or a pharmaceutically acceptable salt thereof in the drug delivery system is stably dispersed in a matrix layer of a pressure-sensitive adhesive in an amorphous state, so that formation of rotigotine crystals can be inhibited, thereby achieving stable release of the drug.

Description

Rotigotine transdermal delivery system that inhibits crystallization and its preparation method and use Technical field

The present invention relates to a system for transdermal drug delivery. More specifically, the present invention relates to a transdermal drug delivery system comprising rotigotine or a pharmaceutically acceptable salt thereof that inhibits crystallization, and a preparation method and use thereof.

Background technique

The transdermal route of drug administration is a route of drug administration that is superior to the oral route of drug administration. It maintains the drug concentration in the blood at a constant level by continuously delivering drugs to the systemic blood system. The transdermal delivery route not only reduces the fluctuations in drug concentration in the blood between peaks and troughs, but also avoids the first-pass effect. In addition, since the transdermal route of administration avoids direct contact between drugs and excipients and the gastrointestinal system, side effects such as nausea and vomiting that are often associated with the oral route of administration are significantly reduced or eliminated. Another advantage of the transdermal route of administration is that it is not affected by diet. Administration can be easily terminated when necessary by removing the transdermal patch from the skin. Furthermore, transdermal patches improve patient compliance by reducing dosing frequency. This is particularly important for elderly patients and pediatric patients.

Common dosage forms for transdermal delivery include transdermal patch preparations. Currently common transdermal drug delivery patch preparations include, but are not limited to, drug reservoir type patches and matrix type patches. Drug reservoir-type patch formulations are patch formulations in which the drug is contained in a reservoir with a drug-permeable substrate surface, and matrix-type patch formulations are patch formulations in which the drug is dissolved or dispersed in a polymer matrix layer. Both types of designs also typically include a backing layer and a release film layer that is removed before use. In addition, patches often contain penetration enhancers and adhesive layers.

In recent years, the advantages of transdermal delivery have enabled many drugs to be effectively administered via the transdermal route. These advances include the development of many physical methods to increase skin permeability and facilitate transdermal drug delivery, e.g. Use iontophoresis, electroporation, ultrasound, or microneedling. However, drugs that can be effectively and safely administered through the skin for 7 days or longer without causing skin adhesion, skin irritation, or sensitization are still limited.

Rotigotine (Rotigotine, rotigotine, rotigotine) is a compound with the following structure (-)-5,6,7,8-tetrahydro-6-[propyl-[2-( 2-Thienyl)ethyl]-amino]-1-naphthol (INN):

Rotigotine is a non-ergolinic D1/D2/D3 dopamine receptor agonist. It has similar receptor characteristics to dopamine in structure, but has higher receptor affinity. Compared with other non-ergot dopamine agonists, rotigotine has significant D1 activity, which contributes to stronger physiological effects. Compared with ergolinic compounds, rotigotine has a very low affinity for the _5HT2B receptor and therefore has a low risk of causing fibrosis. Actions on non-dopaminergic receptors (eg, 5- _HT1A agonism and _A2B antagonism) may contribute to other beneficial effects, such as antidyskinetic activity, neuroprotective activity, and antidepressant effects.

Rotigotine is disclosed as a treatment for patients with Parkinson's disease (described in WO 2002/089777), Parkinson's plus syndrome (described in WO 2005/092331), depression (described in WO 2005/092331) 009424) and restless legs syndrome (described in WO 2003/092677) as well as treatment or prevention of dopaminergic neuron loss (described in WO 2005/063237) and pain treatment (described in PCT/EP2007/005381 description) active agent.

Known pharmaceutical compositions containing rotigotine include: transdermal therapeutic systems or patches (TTS) (described inter alia in WO 99/49852), depot forms (described in WO 02/15903), Iontophoresis devices (described in WO 2004/050083) and intranasal formulations (described in WO 2005/063236).

To date, different transdermal therapeutic systems (TTS) have been described for rotigotine administration.

WO 94/07468 discloses a TTS containing rotigotine hydrochloride as the active substance in a two-phase matrix consisting essentially of a hydrophobic polymer material as a continuous phase and dispersed hydrophilic materials contained therein. A phase is formed, the hydrophilic phase containing essentially the drug and hydrated silica. Silica is said to increase the maximum possible loading of TTS on the hydrophilic salt. Furthermore, the formulations of WO 94/07468 usually contain additional hydrophobic solvents, penetration-promoting substances, dispersants and especially emulsifiers for emulsifying the aqueous solution of the active ingredient in the lipophilic polymer phase. TTS prepared using such a system have been tested in healthy subjects and Parkinson's disease patients. However, satisfactory plasma levels of the drug were not achieved.

Various other TTSs have been described in WO 99/49852. Various other transdermal therapeutic systems have been described in WO 99/49852. The TTS used in this patent application consists of a liner layer that is inert with respect to the matrix components, a self-adhesive matrix layer containing an effective amount of rotigotine or rotigotine hydrochloride, and a protective film that is to be removed before use. . The matrix system consists of a non-aqueous polymeric adhesive system based on acrylates or silicones.

Other TTS for the delivery of rotigotine are disclosed, for example, in EP1 256 339 and WO 2004/012730. These systems use a mixture of at least one high-viscosity and at least one medium-viscosity amine-compatible silicone pressure-sensitive adhesive as the primary adhesive component of the self-adhesive matrix. They will provide better flux rates and adequate rotigotine plasma levels.

Recently, it has been discovered that the systems described above unfortunately exhibit long-term stability problems. If rotigotine crystals form in the self-adhesive matrix during long-term storage, crystal growth can lead to reduced rotigotine release rates, with the risk of eventually falling below the specified value.

Due to the emergence of a new polymorph (Form II) of the medicinal substance rotigotine, crystals form on commercial patches. Attempts to modify the production process met with only very limited success. These patches still require cryogenic storage before application to the skin. Among other things, this leads to more complex application instructions for rotigotine patches, for example, the cooled drug product should be removed from the refrigerator at least 1 hour before application and must be heated when applying the patch The adhesive on the patch.

In general, it is well known in the art that it is very difficult to stabilize the amorphous state of pharmaceutical substances in pharmaceutical dosage forms, including transdermal systems. For example, in the case of rotigotine, the amorphous form is only relatively Stable and easily converted into crystals. In such cases, the self-adhesive matrix as a whole represents a relatively stable solid dispersion.

US 9925150B2 discloses a solid dispersion, which is composed of a silicone pressure-sensitive adhesive as a dispersant and a soluble polyvinylpyrrolidone and rotigotine as a dispersed phase, wherein the weight ratio of rotigotine to polyvinylpyrrolidone is between In the range of about 9:3.5 to about 9:6. The solid dispersion was found to be unstable as rotigotine frequently crystallized out of the solid dispersion. Additionally, the silicone pressure-sensitive adhesive base did not adhere as well to the skin as expected.

Contents of the invention

An object of the present invention is to provide a matrix-type rotigotine transdermal delivery system that inhibits crystallization, which can inhibit the crystallization of rotigotine in the pressure-sensitive adhesive matrix layer. Achieve stable and sustained delivery of rotigotine or a pharmaceutically acceptable salt thereof at a therapeutically effective amount of blood concentration over an extended period of time.

An object of the present invention is to provide a method for preparing a matrix type rotigotine transdermal delivery system. The method heats a wet mixture of rotigotine and pressure-sensitive adhesive to above room temperature and then coats it to produce an adhesive matrix patch that is free of rotigotine crystals. If the wet mixture is not heated, rotigotine will form crystals from the matrix.

An object of the present invention is to provide a matrix-type rotigotine transdermal delivery system that inhibits crystallization. Compared with the matrix layer of rotigotine, a stabilizer that inhibits drug crystallization, and the Bio-PSA silicone adhesive system, the matrix layer is composed of rotigotine, a stabilizer that inhibits drug crystallization, and a polybutylene adhesive. The matrix layer composed of a stabilizer that inhibits drug crystallization and a styrene-isoprene adhesive has better skin adhesion.

It is another object of the present invention to provide a method of treating or preventing a disease that is sensitive to the effects of a dopamine receptor agonist, comprising administering to a subject in need thereof a therapeutically effective amount of a matrix type of rotigoll that inhibits crystallization transdermal drug delivery system.

It is another object of the present invention to provide a method of treating or preventing a disease that is sensitive to the effects of rotigotine, comprising administering to a subject in need thereof a therapeutically effective amount of a matrix type of rotigotine that inhibits crystallization Transdermal drug delivery system.

Another object of the present invention is to provide a method for treating or preventing Parkinson's, Parkinson's superimposed syndrome, depression, restless legs syndrome, pain and dopaminergic neuron loss, which includes administering to a subject in need A therapeutically effective amount of a matrix-type crystallization-inhibiting rotigotine transdermal delivery system is administered.

Another object of the present invention is to provide a therapeutically effective amount of a matrix type rotigotine transdermal delivery system that inhibits crystallization in the preparation of a medicament for the treatment or prevention of diseases sensitive to the effects of dopamine receptor agonists. the use of.

Another object of the present invention is to provide a therapeutically effective amount of a matrix-type rotigotine transdermal delivery system that inhibits crystallization in the preparation of a medicament for the treatment or prevention of diseases that are sensitive to the effects of rotigotine. use.

Another object of the present invention is to provide a therapeutically effective amount of a matrix-type rotigotine transdermal delivery system that inhibits crystallization and is prepared for the treatment or prevention of Parkinson's disease, Parkinson's superimposed syndrome, depression, and restlessness. Use in medicines for leg syndrome, pain, and dopaminergic neuron loss.

Detailed description of the invention

In one embodiment of the present invention, a rotigotine transdermal delivery system is provided, which includes:

1) Backing layer;

2) A matrix layer, which contains rotigotine or a pharmaceutically acceptable salt thereof dispersed in an amorphous state in the matrix layer, a stabilizer that inhibits drug crystallization, and a pressure-sensitive adhesive;

3) Release layer.

In some embodiments, the inhibitory drug crystallization comprises insoluble crospovidone, preferably insoluble crospovidone CL-M, crospovidone CL, crospovidone CL-F, crospovidone Ketone CL-SF.

In some embodiments, the stabilizer that inhibits drug crystallization further contains soluble povidone on the basis of insoluble cross-linked povidone, and the soluble povidone is preferably povidone K30, povidone K90, povidone K12 , one or more of povidone K17, povidone K25, prastone K29/32, and copovidone VA64.

In some embodiments, the weight ratio of rotigotine to insoluble povidone is no higher than 9:40, preferably 9:1-9:24, 9:5-9:22.8, 9:5, 9:6.8, 9:8, 9:10, 9:12, 9:18, 9:20, 9:21, 9:22.8, 9:24.

In some embodiments, the weight ratio of rotigotine to soluble povidone is 9:0.5-9:4, preferably 9:1, 9:2, 9:3, 9:4.

In some embodiments, the stabilizer that inhibits drug crystallization includes polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer, preferably povidone K30, povidone K90, prasitone K29/32, Copovidone VA64, crospovidone CL-M, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate , hydroxypropyl betaide, α, β, λ cyclodextrin, one or more of chitosan, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, or carrageenan.

In some embodiments, the matrix layer further contains other pharmaceutically acceptable excipients. Other pharmaceutically acceptable excipients may be one or more of skin penetration enhancers, thickeners, and cohesion-promoting additives.

In some embodiments, the matrix layer includes the following components relative to the total weight of the matrix layer:

1) The dosage of rotigotine or its pharmaceutically acceptable salt is 3-30%;

2) The dosage of stabilizer that inhibits drug crystallization is 6-40%;

3) The dosage of pressure-sensitive adhesive is 30-90%;

4) Tackifier 0-50%;

5) Skin penetration enhancer 0-30%;

6) Cohesion promoting additive 0-20%;

The total dosage of each component in the matrix layer is 100%.

In some embodiments, the matrix layer further includes a cohesion-promoting additive selected from one or more of the following:

1) Carbohydrate polymer, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl beta German, α, β, λ cyclodextrin, ethyl cellulose, methyl cellulose, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, carrageenan;

2) Acrylic or methacrylic polymer, preferably Eudragit E100, Eudragit PO, Plastoid B, Eudragit S, Eudragit L, Eudragit L-55.

In some embodiments, the pressure-sensitive adhesive is selected from the group consisting of acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene-isoprene-styrene block copolymer adhesives, benzene adhesives, One or more of ethylene-butadiene-styrene copolymer adhesive, silicone adhesive, and acrylic-copolysiloxane copolymer adhesive;

1) The acrylic adhesive is selected from Henkel's Duro-Tak adhesive 387-2051, 387-2054, 387-2353, 87-235A, 87-2852, 87-2074, 87-2677, 387-2516, 387-2287, 387-4287, 387-2510, crosslinked 387-2510, 87-900A, 87-9301, 87-4098, 87-2194, Gelva GMS788, Gelva GMS 9073, Gelva 737, Gelva 2655, Polythick 410-SA (Sanyo Chemical Industry Co., Ltd.);

2) The polyisobutylene adhesive is selected from Oppanol N150, Oppanol B150, Oppanol N100, Oppnaol B100, Oppanol N80, Oppanol B80, Oppanol B10, B11, B12 and low molecular weight polybutene and mineral oil tackifier from Ineos ;

3) The silicone adhesive is selected from DuPont Bio-PSA 7-4100, 7-4200, 7-4202, 7-4300, 7-4302, 7-4400 and 7-4500, 7-4502, 7- 4600Bio-PSA SR7-4400,SRS7-4500,SRS7-4600;

4) The acrylic-co-polysiloxane copolymer adhesive is selected from DuPont Bio-PSA 7-6100, 7-6200 and 7-6300; the Bio-PSA adhesive is dissolved in different solvents, The solvent is selected from one or more of n-heptane, ethyl acetate, toluene or hot melt.

In some embodiments, the content of rotigotine or a pharmaceutically acceptable salt thereof is 5% to 20%, preferably 5% to 15%, or 5% to 12% of the total weight of the matrix layer.

In some embodiments, the content of the stabilizer that inhibits drug crystallization is 6% to 40% of the total weight of the matrix layer, preferably 6% to 30%, 6% to 20%, 6.7%-20%, 6.70%, 8.2%, 9.2%, 10%, 12.5%, 16.65%, 17.50%, 19.00%, 20.00%.

In some embodiments, the content of the pressure-sensitive adhesive is 35% to 90% of the total weight of the matrix layer, preferably 40% to 90%, 70% to 90%, 65%, 70%, 75%, 80%, 90%.

In some embodiments, the tackifier is selected from silicone oil, mineral oil, polybutene, terpenes, and mixtures thereof, preferably light mineral oil. In some embodiments, the amount of tackifier is 0-50%, preferably 0-30%, 0-28% of the total weight of the matrix layer.

In some embodiments, the weight ratio of rotigotine to the tackifier is 9:25-9:40, preferably 9:30-9:35.

In some embodiments, the content of the skin penetration enhancer is 0 to 30% of the total weight of the matrix layer, preferably 5-30%, 5-24%, 10-20%, 12.5-20%.

In some embodiments, the skin penetration enhancer includes optional surfactants.

In some embodiments, the rotigotine transdermal delivery system may further include structures such as a skin contact adhesive layer, a semipermeable membrane, or an organic fabric layer.

In another embodiment of the present invention, a method for the aforementioned rotigotine transdermal delivery system is provided, comprising the following steps:

Step 1. Dissolve the stabilizer in the solvent and mix for 0.1 to 24 hours;

Step 2. Add rotigotine or its pharmaceutically acceptable salt, mix and dissolve until the rotigotine or its pharmaceutically acceptable salt is dispersed in a non-crystalline state;

Step 3. Add pressure-sensitive adhesive and mix evenly to obtain a wet drug mixture;

Step 4. Coat the wet drug mixture on the release film;

Step 5. Dry to remove the solvent to obtain a release film/matrix layer laminate;

Step 6. Laminate the matrix layer to the backing layer.

In some embodiments, the solvent in step 1 includes but is not limited to one or more of toluene, ethanol, isopropyl alcohol, dimethylacetamide, and dimethyl sulfoxide, preferably toluene, ethanol, isopropanol, Propanol or its mixed solvents.

In some embodiments, step 2 includes heating to 35-65°C to bring the drug into solution. The heating temperature in step 2 is preferably 45-55°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C.

In some embodiments, step 3 is to add a pressure-sensitive adhesive heated to 35-65°C and mix evenly to obtain a wet drug mixture. The heating temperature in step 3 is preferably 45-55°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, or 55°C.

In some embodiments, step 4 is to coat the wet drug mixture on the release film while maintaining the temperature at 35-65°C. The heating temperature in step 4 is preferably 45-55°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C.

In another type of embodiment of the present invention, a therapeutically effective amount of a rotigotine transdermal delivery system according to the foregoing is provided in the preparation of a medicament for treating or preventing diseases that are sensitive to the effects of dopamine receptor agonists. the use of.

In some embodiments, the disease is a disease that is sensitive to the effects of rotigotine.

In some embodiments, the disease is Parkinson's disease, Parkinson's disease superimposed syndrome, depression, restless legs syndrome, pain, and dopaminergic neuron loss.

In another embodiment of the present invention, there is provided a method for treating or preventing diseases that are sensitive to the effects of dopamine receptor agonists, which includes administering to a subject in need a therapeutically effective amount of the aforementioned rotigool transdermal drug delivery system.

In some embodiments, the disease is a disease that is sensitive to the effects of rotigotine.

In some embodiments, the disease is Parkinson's disease, Parkinson's disease superimposed syndrome, depression, restless legs syndrome, pain, and dopaminergic neuron loss.

In some embodiments, the rotigotine transdermal delivery system is administered every 1 day, every 3 days, every 7 days, every 10 days, every 14 days, every 21 days, every 28 days.

In some embodiments, the rotigotine transdermal delivery system delivers from about 1 mg to about 18 mg of rotigotine or a pharmaceutically acceptable salt thereof to the blood circulation system of the subject per day, preferably daily. About 2 mg to about 12 mg of rotigotine base or a pharmaceutically acceptable salt thereof is added to the blood circulation system of the subject.

definition

As used herein, the term "pharmaceutically acceptable salt" means a salt suitable for use in contact with a subject (e.g., a human subject) without undue toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, with reasonable benefit/risk ratio and are effective for their intended use.

"Pharmaceutically acceptable salts" as described in the present invention include inorganic acid addition salts and organic acid addition salts, which can be prepared in situ during the final isolation and purification of the compound, or by converting the purified compound in the free base form (eg rotigotine) is prepared by reacting alone with a suitable organic or inorganic acid and isolating the salt thus formed.

As used herein, the term "therapeutically effective amount" means an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition or disorder, (ii) attenuates, ameliorate or eliminate one or more symptoms of a particular disease, disorder, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, disorder, or disorder described herein.

As used herein, the term "about" means plus or minus 10% of the indicated number. For example, "about 10%" may represent a range of 9% to 11%, and "about 1" may represent 0.9-1.1.

As used herein, the term "treatment" refers to clinical intervention that attempts to alter the natural course of the individual being treated, and may be for prevention or in the course of clinical pathology. Desired effects of treatment include, but are not limited to, preventing the occurrence or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, ameliorating or alleviating the disease state, and alleviating or improving prognosis.

As used herein, the term "insoluble cross-linked povidone" is a high-molecular water-insoluble polymer obtained by cross-linking reaction of N-vinyl-2-pyrrolidone. It is a white or nearly white powder, odorless, flowing It has good properties and is insoluble in water and various solvents, as well as in strong acids or alkalis. Non-limiting examples of "insoluble crospovidone" include CL-M, crospovidone CL, crospovidone CL-F, crospovidone CL-SF.

As used herein, the term "backing layer" serves as the upper surface of a transdermal patch and serves as the primary structural element that provides flexibility to the patch. Preferably, the backing layer is substantially impermeable to transdermally administered pharmaceutical compositions. The backing layer is preferably made from a sheet or film of flexible elastic material. The backing layer is preferably air-impermeable. The backing layer used in the patch of the present invention is preferably made of a flexible, biocompatible material that mimics the elastic properties of the skin and conforms to the skin during movement. Non-occlusive backing layers allow the area to breathe (i.e. promote water vapor transmission across the skin surface), whereas occlusive backing layers reduce air/vapor penetration. Preferably, the backing layer of matrix-type transdermal delivery systems (Figures 1-3) is occlusive. Preferably, the backing layer contains synthetic polymers such as polyolefins, polyesters, polyethylene, polyvinylidene chloride and polyurethanes. Preferably, the thickness of the backing layer is from about 0.5 mil to about 5 mils; more preferably, the thickness of the backing layer is from about 1 mil to about 3 mils. Preferably, the oxygen transmission rate is from about 2 cc/m/24hr to about 100 cc/m/24hr. Preferably, the MVTR is from about 0.1 g/m/24hr to about 50g/m/24hr, more preferably, the MVTR is from about 0.3g/m/24hr to about 30g/m/24hr. In a preferred embodiment, the backing layer is an approximately 2.0 mil thick layer of occlusive polyester film (commercially available, e.g., Scotchpak 9733, Scotchpak 9735, and Scotchpak 9723, 3M Drug Delivery Systems, St. Paul Minn.). Scotchpak 9733 consists of polyester and medium density polyethylene/ethylene vinyl acetate heat sealable laminates that are translucent, conformable, occlusive and heat sealable. It can be used in the matrix type transdermal drug delivery system shown in Figures 1-3. More preferably, the backing layer includes a laminate including an aluminum foil layer between polymer film layers, such as Scotchpak 9738 and Scotchpak 1109. When the patch is applied to the skin, the aluminum layer prevents light from coming into contact with the photosensitive rotigotine.

As used herein, the term "release liner" includes, but is not limited to, silicone-coated polyester release liners available from many suppliers, fluoropolymer-coated polyester release liners from 3M, and fluorosilicone-coated polyester Isolation liner.

Detailed ways

In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiment is a module embodiment of the present invention, rather than All examples. Elements and features described in one embodiment of the invention may be combined with elements and features illustrated in one or more other embodiments. It should be noted that for purposes of clarity, representation and description of components and processes known to those of ordinary skill in the art that are not relevant to the present invention have been omitted from the description. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without any creative effort fall within the scope of protection of the present invention.

abbreviation:

PVP K90＝povidone K90, Crospovidone＝crospovidone CL-M, Ascorbyl Palmitate＝ascorbyl palmitate, Sodium Metasulfite＝sodium metabisulfite, Alpha-dl-tocopherol＝α-dl-tocopherol, BHT＝ Butylated hydroxytoluene, Rotigotine = rotigotine, Bio-PSA 7-4502 is a pressure-sensitive adhesive, Duro-Tak 387-2287 is a pressure-sensitive adhesive, Oppanol B12 SFN = polyisobutylene adhesive Agent, Oppanol N100 = Polyisobutylene Adhesive, Bio-PSA 7-4502 is a pressure sensitive adhesive.

Comparative example 1

Weigh the components of each composition according to Table 1 and prepare the prescription. Soluble povidone K90, antioxidant ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C and further mixed at room temperature for 24 hours. Rotigotine was added and completely dissolved at 50 °C as shown by microscopic analysis. Add and mix room temperature silicone adhesives Bio-PSA 7-4302 and Bio-PSA7-4202. The suspension was coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 1, no crystals formed on the patch samples on the first day of storage at room temperature, but crystals were observed on the 30th day of storage at room temperature and the 30th day of storage at 40°C. In this comparative example, the weight ratio of rotigotine to soluble povidone is 9:4.

Comparative example 2

Weigh the components of each composition according to Table 1 and prepare the prescription. Soluble povidone K90, antioxidant ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C and further mixed at room temperature for 24 hours. Rotigotine was added and completely dissolved at 50 °C as shown by microscopic analysis. Add and mix the silicone adhesives Bio-PSA 7-4302 and Bio-PSA7-4202 heated to 50°C. The suspension was maintained in a 50°C water bath, coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 1, no crystals formed on the patch samples stored at room temperature for 14 days, but crystals were observed after 1 month of storage at 40°C. In this comparative example, the weight ratio of rotigotine to soluble povidone is 9:4.

Comparative example 3

Weigh the components of each composition according to Table 1 and prepare the prescription. Soluble povidone K90, antioxidant ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C and further mixed at room temperature for 24 hours. Rotigotine was added and completely dissolved at 50 °C as shown by microscopic analysis. Add and mix the silicone adhesives Bio-PSA 7-4302 and Bio-PSA7-4202 heated to 50°C. The suspension was maintained in a 50°C water bath, coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 1, crystal formation was observed on day 14 of patch samples stored at room temperature, as early as day 2 of storage at 60°C and for 1 month of storage at 40°C. In this comparative example, the weight ratio of rotigotine to soluble povidone is 9:3.

Comparative example 4

Weigh the components of each composition according to Table 1 and prepare the prescription. The antioxidants ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol were dissolved in ethanol. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. Rotigotine was added and completely dissolved at 50 °C as shown by microscopic analysis. Add and mix the silicone adhesives Bio-PSA 7-4302 and Bio-PSA7-4202 heated to 50°C. The suspension was maintained in a 50°C water bath, coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 1, no crystals formed on the patch samples for the first 9 days at room temperature, but crystals were observed as early as day 5 when stored at 60°C and for 1 month when stored at 40°C. In this comparative example, there is no soluble povidone, and the weight ratio of rotigotine to insoluble crospovidone is 9:8.

Comparative example 5

Weigh the components of each composition according to Table 1 and prepare the prescription. The antioxidants ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol were dissolved in ethanol at 50°C. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add and mix room temperature silicone adhesives Bio-PSA 7-4302 and Bio-PSA7-4202. The suspension was maintained at room temperature, coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 1, no crystals formed on the patch samples during the first 8 days of storage at room temperature, but crystals were observed after 3 months of storage at room temperature and 3 months of storage at 40°C. In this comparative example, there is no soluble povidone, and the weight ratio of rotigotine to insoluble crospovidone is approximately 9:20.

Example 1

Weigh the components of each composition according to Table 1 and prepare the prescription. Soluble povidone, antioxidant ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol were dissolved in ethanol at 50°C. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add and mix the silicone adhesives Bio-PSA 7-4302 and Bio-PSA7-4202 heated to 50°C. The suspension was incubated at 50°C, coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 1, there was no crystal formation in the patch samples stored at room temperature for 9 months and at 40°C for 6 months. In this embodiment, the weight ratio of rotigotine to soluble povidone is 9:3, and the ratio of rotigotine to insoluble cross-linked povidone is 9:6.8.

Example 2

Weigh the components of each composition according to Table 1 and prepare the prescription. Soluble povidone, antioxidant ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol were dissolved in ethanol at 50°C. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add and mix the silicone adhesives Bio-PSA 7-4302 and Bio-PSA7-4202 heated to 50°C. The suspension was incubated at 50°C, coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 1, there was no crystal formation in the patch samples stored at room temperature for 9 months and at 40°C for 6 months. In this embodiment, the weight ratio of rotigotine to soluble povidone is 9:3, and the weight ratio of rotigotine to insoluble cross-linked povidone is 9:8.

Example 3

Weigh the components of each composition according to Table 1 and prepare the prescription. Soluble povidone, antioxidant ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol were dissolved in ethanol at 50°C. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add and mix the silicone adhesives Bio-PSA 7-4302 and Bio-PSA7-4202 heated to 50°C. The suspension was incubated at 50°C, coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 1, there was no crystal formation in the patch samples stored at room temperature for 9 months and at 40°C for 6 months. In this embodiment, the weight ratio of rotigotine to soluble povidone is 9:3, and the weight ratio of rotigotine to insoluble cross-linked povidone is 9:9.

Table 1. Comparative Examples 1 to 5, Examples 1 to 3

Comparative example 6

Weigh the components of each composition according to Table 2 and prepare the prescription. The antioxidants ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in toluene at 50°C. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add and mix room temperature solutions of the polyisobutylene adhesives Oppanol B12 and Oppanol N100 in toluene. The suspension was coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 2, crystal formation was observed as early as day 8 for patch samples stored at 40°C. In this example, there is no soluble povidone and the ratio of rotigotine to insoluble crospovidone is 9:3. In this comparative example, the wet mixture was maintained at room temperature, ie, was not heated above room temperature, to maintain dissolution of rotigotine in the wet mixture.

Comparative Example 7 to Comparative Example 11

The patch samples of Comparative Examples 7 to 11 were prepared using a method similar to Comparative Example 6. Weigh the components of each composition according to Table 2 and prepare the prescription. The amount of insoluble crospovidone was increased to 10%, 13%, 16.65%, 18% and 20% respectively. The patch samples of Comparative Examples 7 to 11 all formed crystals, but as the amount of insoluble crospovidone increased, the formation of crystals became more and more delayed. In these comparative examples, the wet mixture was maintained at room temperature, ie, was not heated above room temperature, to maintain dissolution of rotigotine in the wet mixture.

Example 4

Weigh the components of each composition according to Table 2 and prepare the prescription. The antioxidants ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in toluene at 50°C. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add and mix a solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in toluene heated to 50°C. The suspension was incubated at 50°C, coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 2, no crystals were observed in the patch samples stored at 60°C for 10 days and at 40°C for 1 month. In this example, there is no soluble povidone and the ratio of rotigotine to insoluble crospovidone is 9:21. In this example, the wet mixture was maintained at 50°C to maintain dissolution of rotigotine in the wet mixture prior to coating.

Example 5

Weigh the components of each composition according to Table 2 and prepare the prescription. Example 5 was prepared using a method similar to Example 4. As shown in Table 2, no crystals were observed on the patch samples on the 10th day of storage at 60°C and after 1 month of storage at 40°C. In this example, there is no soluble povidone and the ratio of rotigotine to insoluble crospovidone is 7.5:20 or 9:24. In this example, the wet mixture was maintained at 50°C to maintain dissolution of rotigotine in the wet mixture prior to coating.

Example 6

Weigh the components of each composition according to Table 2 and prepare the prescription. The antioxidants ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in isopropyl alcohol at 50°C. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add and mix a solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in n-heptane heated to 50°C. The suspension was incubated at 50°C, coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 2, no crystals were observed on the patch samples stored at 60°C on the 10th day. In this example, there is no soluble povidone and the ratio of rotigotine to insoluble crospovidone is 7.5:20 or 9:24. In this example, the wet mixture was maintained at 50°C to maintain dissolution of rotigotine in the wet mixture prior to coating.

Comparative example 12

Weigh the components of each composition according to Table 2 and prepare the prescription. Dissolve povidone K90, ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol in isopropyl alcohol at 50°C. Insoluble cross-linked povidone CL-M is mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add and mix a solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in n-heptane heated to 50°C. The suspension was incubated at 50°C, coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 2, crystallization was observed on the 3rd day when the patch samples were stored at room temperature. In this embodiment, the weight ratio of rotigotine to soluble povidone is 9:3, and the weight ratio of rotigotine to insoluble cross-linked povidone is 9:3.6.

Example 7

Weigh the components of each composition according to Table 2 and prepare the prescription. Dissolve povidone K90, ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol in isopropyl alcohol at 50°C. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add and mix a solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in n-heptane heated to 50°C. The suspension was incubated at 50°C, coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 2, no crystals were observed on the patch samples on the 10th day of storage at 60°C, and no crystals were observed on the patch samples after 1 month of storage at 40°C. In this embodiment, the weight ratio of rotigotine to crospovidone is 9:3, and the weight ratio of rotigotine to insoluble crospovidone is 9:12.

Example 8

Weigh the components of each composition according to Table 2 and prepare the prescription. Dissolve povidone K90, ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol in isopropyl alcohol at 50°C. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add and mix a solution of the polyisobutylene binders Oppanol B12 and Oppanol N100 in n-heptane heated to 50°C. The suspension was incubated at 50°C, coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 2, no crystals were observed on the patch sample on the 10th day of storage at 60°C, and no crystals were observed on the patch sample after 1 month of storage at 40°C. In this embodiment, the weight ratio of rotigotine to crospovidone is 9:3, and the weight ratio of rotigotine to insoluble crospovidone is 9:18.

Table 2. Comparative Examples 6 to 12, Examples 4 to 8

Comparative example 13

Weigh the components of each composition according to Table 3 and prepare the prescription. Ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add Bio-PSA 7-4502 and mix. The suspension was coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 3, crystals were observed on the patch samples stored at room temperature for 6 months and on the 22nd day of storage at 40°C. In this example, the ratio of rotigotine to insoluble crospovidone is 7.5:6 or 9:7.2.

Comparative example 14

Weigh the components of each composition according to Table 3 and prepare the prescription. Ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add Bio-PSA 7-4502 and mix. The suspension was coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 3, crystals were observed on the 62nd day of storage of patch samples at 40°C. In this example, the ratio of rotigotine to insoluble crospovidone is 7.5:10 or 9:12.

Comparative example 15

Weigh the components of each composition according to Table 3 and prepare the prescription. Soluble povidone K90, ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C and then mixed at room temperature for 24 hours. The solution was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add Bio-PSA 7-4502 and mix. The suspension was coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 3, crystals were observed in patch samples stored at room temperature for 6 months. In this example, the weight ratio of rotigotine to soluble povidone is 9:4.

Example 9

Weigh the components of each composition according to Table 3 and prepare the prescription. Ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C. Insoluble cross-linked povidone CL-M was mixed at room temperature for 24 hours. The solution was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add Bio-PSA 7-4502 and mix. The suspension was coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 3, no crystals were observed in the patch samples stored at room temperature for 6 months and at 40°C for 6 months. In this example, the ratio of rotigotine to insoluble soluble crospovidone is 9:20.

Example 10

Weigh the components of each composition according to Table 3 and prepare the prescription. The formulation in Example 10 was prepared using the same method as Example 9. As shown in Table 3, no crystals were observed in the patch samples stored at room temperature for 6 months and at 40°C for 6 months. In this example, the weight ratio of rotigotine to insoluble crospovidone is 9:22.8.

Example 11

Weigh the components of each composition according to Table 3 and prepare the prescription. Soluble povidone K90, ascorbyl palmitate, sodium metabisulfite and α-dl-tocopherol were dissolved in ethanol at 50°C. Crospovidone CL-M was mixed at room temperature for 24 hours. The suspension was heated to 50°C and rotigotine was added and completely dissolved as shown by microscopic analysis. Add and mix Bio-PSA 7-4502 and Duro-Tak 387-2287. The suspension was coated on a release film and dried at 40°C for 4 min and 85°C for 4 min to remove the solvent. As shown in Table 3, no crystals were observed in the patch samples stored at room temperature for 11 months and at 40°C for 6 months. In this embodiment, the weight ratio of rotigotine to insoluble povidone is 9:5, and the weight ratio of rotigotine to soluble povidone is 9:3.

Examples 12 to 14

Weigh the components of each composition according to Table 3 and prepare the prescription. The formulations of Examples 12 to 14 were prepared using the same method as Formulation 11 of Example 11. As shown in Table 3, no crystals were observed in the patch samples stored at room temperature for 9 months and at 40°C for 6 months.

Table 3. Comparative Examples 13 to 15 and Examples 9 to 14

Claims (25)

A rotigotine transdermal drug delivery system, which includes: 1) Backing layer; 2) A matrix layer, which contains rotigotine or a pharmaceutically acceptable salt thereof dispersed in an amorphous state in the matrix layer, a stabilizer that inhibits drug crystallization, and a pressure-sensitive adhesive; 3) Release layer. The rotigotine transdermal drug delivery system according to claim 1, wherein the inhibitory drug crystallization includes insoluble cross-linked povidone, preferably insoluble cross-linked povidone CL-M, cross-linked povidone CL, cross-linked povidone CL, Copovidone CL-F, crospovidone CL-SF. The rotigotine transdermal drug delivery system according to claim 2, wherein the stabilizer that inhibits drug crystallization further contains soluble povidone on the basis of insoluble cross-linked povidone, and the soluble povidone is preferably polyvidone. One or more of povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, prastone K29/32, and copovidone VA64. The rotigotine transdermal delivery system according to claim 3, wherein the weight ratio of rotigotine to insoluble povidone is not higher than 9:40, preferably 9:1-9:24, 9:5- 9:22.8, 9:5, 9:6.8, 9:8, 9:10, 9:12, 9:18, 9:20, 9:21, 9:22.8, 9:24. The rotigotine transdermal delivery system according to claim 3 or 4, wherein the ratio of rotigotine to soluble povidone is 9:0.5-9:4, preferably 9:1, 9:2, 9 :3, 9:4. The rotigotine transdermal drug delivery system according to claim 1, wherein the stabilizer that inhibits drug crystallization includes polyvinylpyrrolidone or cross-linked polyvinylpyrrolidone or vinylpyrrolidone copolymer, preferably povidone K30, polyvinylpyrrolidone Viton K90, prastone K29/32, copovidone VA64, crospovidone CL-M, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate , hydroxypropyl methylcellulose phthalate, hydroxypropyl betaide, alpha, beta, lambda cyclodextrin, chitosan, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, or One or more carrageenans. The rotigotine transdermal delivery system according to any one of claims 1 to 6, wherein the matrix layer further contains other pharmaceutically acceptable auxiliary materials, and the other pharmaceutically acceptable auxiliary materials are preferably skin One or more of penetration accelerators, tackifiers, and cohesion-promoting additives. The rotigotine transdermal drug delivery system according to any one of claims 1 to 7, relative to the total weight of the matrix layer, the matrix layer includes the following components: 1) The dosage of rotigotine or its pharmaceutically acceptable salt is 3-30%; 2) The dosage of stabilizer that inhibits drug crystallization is 6-40%; 3) The dosage of pressure-sensitive adhesive is 30-90%; 4) Tackifier 0-50%; 5) Skin penetration enhancer 0-30%; 6) Cohesion promoting additive 0-20%; The total dosage of each component in the matrix layer is 100%. The rotigotine transdermal drug delivery system according to any one of claims 1 to 7, the matrix layer further includes a cohesion-promoting additive, and the cohesion-promoting additive is selected from one or more of the following: 1) Carbohydrate polymer, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl beta German, α, β, λ cyclodextrin, ethyl cellulose, methyl cellulose, chitosan, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, carrageenan; 2) Acrylic or methacrylic polymer, preferably Eudragit E100, Eudragit PO, Plastoid B, Eudragit S, Eudragit L, Eudragit L-55. The rotigotine transdermal delivery system according to any one of claims 1 to 9, wherein the pressure-sensitive adhesive is selected from the group consisting of acrylic adhesive, methacrylic adhesive, and polyisobutylene adhesive. , styrene-isoprene-styrene block copolymer adhesive, styrene-butadiene-styrene copolymer adhesive, silicone adhesive, acrylic-copolysiloxane copolymer adhesive One or more mixtures; 1) The acrylic adhesive is selected from Henkel's Duro-Tak adhesive 387-2051, 387-2054, 387-2353, 87-235A, 87-2852, 87-2074, 87-2677, 387-2516, 387-2287, 387-4287, 387-2510, crosslinked 387-2510, 87-900A, 87-9301, 87-4098, 87-2194, Gelva GMS788, Gelva GMS 9073, Gelva 737, Gelva 2655, Polythick 410-SA (Sanyo Chemical Industry Co., Ltd.); 2) The polyisobutylene adhesive is selected from Oppanol N150, Oppanol B150, Oppanol N100, Oppnaol B100, Oppanol N80, Oppanol B80, Oppanol B10, B11, B12 and low molecular weight polybutene and mineral oil tackifier from Ineos ; 3) The silicone adhesive is selected from DuPont Bio-PSA 7-4100, 7-4200, 7-4202, 7-4300, 7-4302, 7-4400 and 7-4500, 7-4502, 7- 4600Bio-PSA SR7-4400,SRS7-4500,SRS7-4600; 4) The acrylic-co-polysiloxane copolymer adhesive is selected from DuPont Bio-PSA7-6100, 7-6200 and 7-6300; the Bio-PSA adhesive is dissolved in different solvents, so The solvent is selected from one or more of n-heptane, ethyl acetate, toluene or hot melt. The rotigotine transdermal delivery system according to any one of claims 1 to 10, wherein the content of rotigotine or a pharmaceutically acceptable salt thereof is 5% to 20% of the total weight of the matrix layer , preferably 5% to 15%, 5% to 12%, 7.5%. The rotigotine transdermal delivery system according to any one of claims 1 to 11, wherein the content of the stabilizer that inhibits drug crystallization is 6% to 40% of the total weight of the matrix layer, preferably 6% to 30% %, 6% to 20%, 6.7%-20%, 6.70%, 8.2%, 9.2%, 10%, 12.5%, 16.65%, 17.50%, 19.00%, 20.00%. The rotigotine transdermal delivery system according to any one of claims 1 to 12, wherein the content of the pressure-sensitive adhesive is 35% to 90% of the total weight of the matrix layer, preferably 40% to 90% , 70% to 90%, 65%, 70%, 75%, 80%, 90%. The rotigotine transdermal delivery system according to any one of claims 7-13, wherein the viscosity increasing agent is selected from the group consisting of silicone oil, mineral oil, polybutene, terpenes and mixtures thereof, preferably light mineral oil; Further, the amount of tackifier is 0-50%, preferably 0-30%, of the total weight of the matrix layer. The rotigotine transdermal delivery system according to any one of claims 7-14, wherein the weight ratio of rotigotine to the thickening agent is 9:25-9:40, preferably 9: 30-9:35. A method for preparing the rotigotine transdermal delivery system according to any one of claims 1-15, comprising: Step 1. Dissolve the stabilizer in the solvent and mix for 0.1 hour to 24 hours; preferably, the solvent includes but is not limited to one of toluene, ethanol, isopropyl alcohol, dimethylacetamide, and dimethyl sulfoxide. One or more, the solvent is more preferably toluene, ethanol, isopropyl alcohol or a mixed solvent thereof; Step 2. Add rotigotine or its pharmaceutically acceptable salt, mix and dissolve until the rotigotine or its pharmaceutically acceptable salt is dispersed in a non-crystalline state; Step 3. Add pressure-sensitive adhesive and mix evenly to obtain a wet drug mixture; Step 4. Coat the wet drug mixture on the release film; Step 5. Dry to remove the solvent to obtain a release film/matrix layer laminate; Step 6. Laminate the matrix layer to the backing layer. The method according to claim 16, wherein step 2 includes the step of heating to 35-65°C to bring the drug into a dissolved state; the heating temperature is preferably 45-55°C. The method according to claim 16 or 17, wherein the step 3 is to add a pressure-sensitive adhesive heated to 35-65°C and mix evenly to obtain a wet drug mixture; the heating temperature is preferably 45-55°C. The method according to any one of claims 16-18, wherein step 4 is to coat the wet drug mixture on the release film at 35-65°C; the heating temperature is preferably 45-55°C. Use of a therapeutically effective amount of the rotigotine transdermal delivery system according to any one of claims 1 to 19 in the preparation of a medicament for treating or preventing diseases that are sensitive to the effects of dopamine receptor agonists. The use according to claim 20, wherein the disease is a disease sensitive to the effects of rotigotine. The use according to claim 20, wherein the disease is Parkinson's disease, Parkinson's syndrome, depression, restless legs syndrome, pain and dopaminergic neuron loss. A method of treating or preventing a disease that is sensitive to the effects of a dopamine receptor agonist, comprising administering to a subject in need a therapeutically effective amount of rotigotine according to any one of claims 1-19 Transdermal drug delivery system. The method of claim 23, wherein the disease is a disease sensitive to the effects of rotigotine. The method of claim 23, wherein the disease is Parkinson's disease, Parkinson's disease superimposed syndrome, depression, restless legs syndrome, pain and dopaminergic neuron loss.