Stable rotigotine transdermal drug delivery kit as well as preparation method and application thereof

Abstract

The invention relates to a stable rotigotine transdermal drug delivery kit. More specifically, the present invention relates to a transdermal drug delivery kit containing rotigotine or a pharmaceutically acceptable salt thereof, and a preparation method and use thereof, and the transdermal drug delivery kit maintains the content of related substances such as oxide impurities in a transdermal patch at an extremely low level.

Description

[0001] This application is a divisional application of the invention patent application with the application date of January 4, 2023, the application number of 202310008078.7, and the invention name of "Stable Rotigotine Transdermal Administration Kit and Its Preparation Method and Use". Technical Field

[0002] The present invention relates to a stable rotigotine transdermal administration kit. More specifically, the present invention relates to a transdermal administration kit of rotigotine or a pharmaceutically acceptable salt thereof, and its preparation method and use. Background Art

[0003] The transdermal administration route is a superior route of administration compared to the oral administration route. It continuously delivers drugs to the systemic blood system, maintaining the drug concentration in the blood at a constant level. The transdermal administration route not only reduces the fluctuations in the drug concentration in the blood between peaks and valleys but also avoids the first-pass effect. In addition, since the transdermal administration route avoids the direct contact of drugs and excipients with the gastrointestinal system, it significantly reduces or eliminates side effects such as nausea and vomiting that are often associated with the oral administration route. Another advantage of the transdermal administration route is that it is not affected by diet. When necessary, it is easy to terminate drug administration by removing the transdermal patch from the skin. Moreover, the transdermal patch improves patient compliance by reducing the dosing frequency. This is particularly important for elderly patients and pediatric patients.

[0004] In recent years, the advantages of transdermal administration have enabled many drugs to be effectively administered through the transdermal route. These advancements include the development of many physical methods to increase skin permeability and promote transdermal drug delivery, such as iontophoresis, electroporation, ultrasound, or microneedles. However, there are still limited drugs that can be effectively and safely continuously administered through the skin for 7 days or longer without causing skin adhesion, skin irritation, or sensitization.

[0005] Rotigotine is a compound with the following structure (-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-naphthol (INN):

[0006]

[0007] Rotigotine has been disclosed as an active agent for treating patients with Parkinson's disease, Parkinson's plus syndrome, depression, and restless legs syndrome, as well as an active agent for treating or preventing dopaminergic neuron loss and pain treatment.

[0008] Known pharmaceutical compositions containing rotigotine include: transdermal therapeutic systems or patches (TTS), depot forms, iontophoretic devices, and intranasal preparations.

[0009] To date, different transdermal therapeutic systems (TTS) for rotigotine administration have been described.

[0010] WO 94 / 07468 discloses a transdermal delivery system (TTS) containing rotigotine hydrochloride as the active substance in a two-phase matrix, which is essentially formed by a hydrophobic polymer material as the continuous phase and a dispersed hydrophilic phase contained therein. The hydrophilic phase mainly contains the drug and hydrated silica. It is alleged that silica increases the maximum possible loading of the TTS for the hydrophilic salt. The formulations of WO 94 / 07468 usually contain additional hydrophobic solvents, penetration enhancers, dispersants, and especially emulsifiers. The emulsifier is used to emulsify the aqueous solution of the active component in the lipophilic polymer phase. TTS prepared using such systems have been tested in healthy subjects and Parkinson's disease patients. However, satisfactory drug plasma levels have not been achieved.

[0011] In WO 99 / 49852, different other transdermal therapeutic systems have been described, which comprise: a liner layer inert relative to the matrix components, a self-adhesive matrix layer containing an effective amount of rotigotine or rotigotine hydrochloride, and a protective film to be removed before use. The matrix system consists of a non-aqueous polymer adhesive system based on acrylate or silicone.

[0012] US 9925150B2 discloses a solid dispersion composed of a silicone pressure-sensitive adhesive as the dispersant, soluble polyvinylpyrrolidone and rotigotine as the dispersed phase, wherein the weight ratio of rotigotine to polyvinylpyrrolidone is in the range of about 9:3.5 to about 9:6. Comparative Examples 1-3 of this application found that such solid dispersions are unstable because rotigotine often crystallizes out of the solid dispersion. In addition, the skin adhesion of the silicone pressure-sensitive adhesive matrix is not as good as expected.

[0013] US 9226902B discloses a transdermal drug delivery system of amorphous rotigotine, wherein the stabilizer is soluble polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, or a combination thereof, and the weight ratio of the stabilizer to rotigotine is about 0.5 or higher.

[0014] Generally speaking, it is well known in the art that it is very difficult to stabilize the amorphous state of the medicinal substance in pharmaceutical dosage forms (including transdermal systems). The amorphous form of rotigotine is only relatively stable and easily converts into the crystalline form in transdermal preparations.

[0015] It has been found that the above-mentioned system unfortunately exhibits long-term stability problems. If rotigotine crystals form in the self-adhesive matrix during long-term storage, crystal growth can lead to a reduced rotigotine release rate, with the risk of ultimately falling below the specified value.

[0016] Due to the emergence of a new polymorph (Form II) of rotigotine, crystals will form on commercial patches. Attempts to modify the production process have only achieved very limited success. These patches still need to be stored at low temperature before being applied to the skin. This results in 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 when applying the patch, the adhesive on the patch must be heated.

[0017] None of the prior arts disclose a method for improving the stability of a rotigotine transdermal delivery formulation. Therefore, there is an urgent need for a rotigotine transdermal delivery system that can maintain the stability of the active substance for a longer period of time, with the related substance content maintained in a very low range, meeting the requirements of ICH Q3B. Summary of the Invention

[0018] This application has found that there is a problem of crystallization of rotigotine in the transdermal patch formulation. To inhibit the crystallization of rotigotine, this application uses crystallization inhibitors povidone, copovidone, and crospovidone CL-M in the patch formulation. Merely using soluble povidone is not sufficient to well inhibit the crystallization of rotigotine in the transdermal patch formulation. After using cross-linked povidone to replace part or all of the water-soluble povidone, the problem of crystallization of rotigotine in the transdermal patch can be well inhibited.

[0019] This application further finds that rotigotine is particularly unstable in the transdermal patch formulation containing peroxide excipients. The peroxide excipients include, for example, pressure-sensitive acrylic adhesives, povidone, copovidone, and crospovidone CL-M. Under the conventional storage conditions of the drug product, rotigotine in the transdermal patch formulation is easily degraded by peroxide, generating N-oxide (EP impurity E), and the N-oxide further decomposes into other substances (EP impurity C, EP impurity B, and EP impurity K, etc.) related substances, resulting in the unusability of the transdermal patch formulation.

[0020]

[0021] The inventors of this application also find that adding a combination of antioxidants to the drug matrix layer of the transdermal patch can reduce the generation of related substances and inhibit the degradation of rotigotine by peroxide.

[0022] The inventors of this application also unexpectedly find that filling an inert gas, such as nitrogen, in the packaging container (such as a packaging bag) of the patch formulation with antioxidants added to the matrix can further inhibit the degradation of rotigotine.

[0023] The applicant more surprisingly found that on the basis of filling nitrogen, adding a moisture absorbent that does not contact the patch matrix layer in the package can further inhibit the oxidative degradation of rotigotine.

[0024] The inventor also unexpectedly found that on the basis of filling nitrogen or a combination of a filling gas and a moisture absorbent in contact with the patch matrix layer, further adding an oxygen scavenger that does not contact the patch matrix layer in the packaging bag will not cause a decrease in stability. Unexpectedly, the moisture absorbent that does not contact the patch matrix layer reduces the generation of oxidative impurities.

[0025] Therefore, an object of the present invention is to provide a stable matrix-type rotigotine transdermal administration preparation and its kit, in which rotigotine does not crystallize after being stored for a period of time.

[0026] An object of the present invention is to provide a stable matrix-type rotigotine transdermal administration preparation and its kit, the related substance content of which is maintained at an extremely low level after being stored for a period of time, and which can continuously deliver rotigotine or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration for an extended period of time.

[0027] An object of the present invention is to provide a stable matrix-type rotigotine transdermal administration preparation and its kit, which can inhibit the degradation of rotigotine by peroxides in the excipient.

[0028] Another object of the present invention is to provide a method for preparing a matrix-type rotigotine transdermal administration preparation and its kit. The matrix-type rotigotine transdermal administration preparation and its kit prepared by this method do not crystallize rotigotine after being stored for a period of time, the related substance content is maintained at an extremely low level, and can continuously deliver rotigotine or a pharmaceutically acceptable salt thereof at a therapeutically effective blood drug concentration for an extended period of time.

[0029] Another object of the present invention is to provide a method for treating or preventing a disease sensitive to the action of a dopamine receptor agonist, which comprises administering to a subject in need a therapeutically effective amount of a matrix-type rotigotine transdermal administration kit that inhibits crystallization.

[0030] Another object of the present invention is to provide a method for treating or preventing a disease sensitive to the action of rotigotine, which comprises administering to a subject in need a therapeutically effective amount of a matrix-type rotigotine transdermal administration kit that inhibits crystallization.

[0031] Another object of the present invention is to provide a method for treating or preventing Parkinson's disease, Parkinson's plus syndrome, depression, restless legs syndrome, pain, and dopaminergic neuron loss, which comprises administering to a subject in need thereof a therapeutically effective amount of a matrix-type rotigotine transdermal delivery kit that inhibits crystallization.

[0032] Another object of the present invention is to provide the use of a therapeutically effective amount of a matrix-type rotigotine transdermal delivery kit that inhibits crystallization in the preparation of a medicament for treating or preventing a disease sensitive to the action of a dopamine receptor agonist.

[0033] Another object of the present invention is to provide the use of a therapeutically effective amount of a matrix-type rotigotine transdermal delivery kit that inhibits crystallization in the preparation of a medicament for treating or preventing a disease sensitive to the action of rotigotine.

[0034] Another object of the present invention is to provide the use of a therapeutically effective amount of a matrix-type rotigotine transdermal delivery kit that inhibits crystallization in the preparation of a medicament for treating or preventing Parkinson's disease, Parkinson's plus syndrome, depression, restless legs syndrome, pain, and dopaminergic neuron loss. DETAILED DESCRIPTION OF THE INVENTION

[0036] The first aspect of the present invention provides a rotigotine transdermal delivery kit, which comprises a transdermal patch, and the transdermal patch comprises:

[0037] 1) a backing layer;

[0038] 2) a matrix layer, which contains rotigotine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a stabilizer that inhibits drug crystallization, an antioxidant, and a pressure-sensitive adhesive; and

[0039] 3) a release liner;

[0040] wherein the transdermal patch is packaged in a packaging container.

[0041] In some embodiments, the packaging container is filled with an inert gas. The inert gas is preferably nitrogen, and preferably filling with nitrogen reduces oxygen to less than about 3.0%, and more preferably filling with an inert gas reduces oxygen to about 2.0%, 1.0%, 0.5%, 0.2%, 0.15%, 0.1%, 0.05%, 0.01% or less.

[0042] In some embodiments, the stabilizer for inhibiting drug crystallization contains peroxide; preferably, the stabilizer for inhibiting drug crystallization containing peroxide comprises insoluble crospovidone; more preferably, the insoluble crospovidone is selected from one or more of insoluble crospovidone CL-M, crospovidone CL, crospovidone CL-F, and crospovidone CL-SF.

[0043] In some embodiments, the stabilizer for inhibiting drug crystallization further comprises soluble polyvinylpyrrolidone on the basis of insoluble crospovidone, and the soluble polyvinylpyrrolidone is preferably one or more of polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, plasdone K29 / 32, and copolyvidone VA64.

[0044] In some embodiments, the weight ratio of rotigotine to insoluble polyvinylpyrrolidone 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, 16.5, 9:18, 9:20, 9:21, 9:22.8, 9:24, 9:27.

[0045] In some embodiments, the weight ratio of rotigotine to soluble polyvinylpyrrolidone is 9:0.5 - 9:10, and specifically, it can be selected from 9:1, 9:2, 9:3, 9:4, 9:5, 9:6, 9:7, 9:8, 9:9, 9:10.

[0046] In some embodiments, a moisture absorbent that does not contact the patch matrix layer is further added to the packaging container. The moisture absorbent is selected from one or more of calcium chloride, calcium oxide, barium oxide, calcium sulfate, molecular sieve, sodium sulfate, magnesium sulfate, silicon dioxide, silica gel, potassium hydroxide, potassium carbonate, and phosphorus pentoxide.

[0047] In some embodiments, an oxygen scavenger that does not contact the patch matrix layer is further added to the packaging container. The main components of the oxygen scavenger are selected from iron powder and sodium chloride, ferrous carbonate and metal halide, ascorbate and sodium bicarbonate; preferably, the combination of iron powder and sodium chloride, such as the oxygen scavenger iron used in the examples.

[0048] In some embodiments, the moisture absorbent and / or the oxygen scavenger are respectively packaged in a breathable film. Preferably, the moisture absorbent and / or the oxygen scavenger packaged in the breathable film are respectively adhered to or placed on the heat-sealing layer in the packaging container or the moisture absorbent and / or the oxygen scavenger are uniformly included in the heat-sealing layer.

[0049] In some embodiments, the packaging container has low oxygen permeability and low moisture permeability; preferably, it is a metal tray, a plastic tray, or a packaging bag made of a multi-layer laminate material comprising a paper layer, an aluminum foil layer, and a heat-sealable inner layer.

[0050] In some embodiments, the antioxidant in the matrix is selected from ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, a small amount of propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sodium thiosulfate, DL-α-tocopherol (vitamin E); the antioxidant further comprises a chelating agent as a co-antioxidant, including one or more of citric acid, tartaric acid, calcium disodium edetate, disodium edetate and EDTA.

[0051] In some embodiments, the combination of antioxidants in the matrix is selected from: the combination of ascorbyl palmitate, sodium metabisulfite and DL-α-tocopherol (vitamin E), or the combination of ascorbyl palmitate, sodium metabisulfite, DL-α-tocopherol (vitamin E) and BHT.

[0052] In some embodiments, relative to the total weight of the matrix layer, the matrix layer comprises the following components:

[0053] 1) The dosage of rotigotine or a pharmaceutically acceptable salt thereof is 3-30%;

[0054] 2) The dosage of a stabilizer that inhibits drug crystallization is 6-40%;

[0055] 3) The dosage of the antioxidant is 0.001%-10%;

[0056] 4) The dosage of the pressure-sensitive adhesive is 30-95%;

[0057] 5) The dosage of the tackifier is 0-50%;

[0058] 6) The dosage of the skin penetration enhancer is 0-30%;

[0059] 7) The dosage of the cohesion-promoting additive is 0-20%;

[0060] The total dosage of each component in the matrix layer is 100%.

[0061] In some embodiments, the pressure-sensitive adhesive is selected from one or more of acrylic adhesives, silicone adhesives, acrylic-silicone copolymer adhesives, polybutene adhesives, styrene-isoprene-butene copolymers and styrene-butadiene-styrene copolymers.

[0062] In some embodiments, the tackifier is selected from silicone oil, light mineral oil, polybutene, triethyl citrate, terpenes and mixtures thereof.

[0063] In some embodiments, 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%, or 5% to 12%.

[0064] 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%, 13%, 16.65%, 17.50%, 19.00%, 20.00%, 25%, 30%.

[0065] In some embodiments, the dosage of cross-linked polyvinylpyrrolidone that inhibits drug crystallization is 6% to 40%, preferably 6% to 30%, 6% to 20%, 6.7% - 20%, 6.70%, 8.2%, 9.2%, 10%, 12.5%, 13%, 16.65%, 17.50%, 19.00%, 20.00%, 25%, 30%.

[0066] In some embodiments, the dosage of polyvinylpyrrolidone that inhibits drug crystallization is 0 - 10%. Specifically, it can be selected from 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%.

[0067] 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%.

[0068] In some embodiments, the dosage of the tackifier is 0 - 50% of the total weight of the matrix layer, preferably 0 - 30%, 0 - 28%.

[0069] In some embodiments, the dosage of each antioxidant is 0.001% - 10%, preferably 0.0015% - 5%. The specific dosage of each antioxidant can be selected from 0.0015%, 0.002%, 0.004%, 0.006%, 0.008%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%.

[0070] In some embodiments, the total dosage of multiple antioxidants is 0.001% - 10%. Specifically, it can be selected from 5%, 1%, 0.5%, 0.25%, 0.1%, 0.075%, 0.05%, 0.025%, 0.01%, 0.0075%, 0.005%, 0.0025%, 0.002%, 0.0015%.

[0071] In some embodiments, the weight ratio of rotigotine to the tackifier is 9:25 - 9:40, preferably 9:30 - 9:35.

[0072] On the other hand, the present invention provides a method for preparing the aforementioned transdermal drug delivery kit, comprising the following steps:

[0073] Step 1. Dissolve the antioxidant in a solvent, dissolve or suspend the stabilizer for inhibiting drug crystallization in the solvent, and mix for 0.1 hour to 24 hours; preferably, the solvent includes but is not limited to one or more of toluene, ethanol, isopropanol, dimethylacetamide, dimethyl sulfoxide, and n-heptane, and the solvent is more preferably toluene, ethanol, isopropanol, or a mixed solvent thereof.

[0074] Step 2. Add rotigotine or a pharmaceutically acceptable salt thereof, and mix and dissolve until rotigotine or a pharmaceutically acceptable salt thereof is dispersed in a non-crystalline state.

[0075] Step 3. Add a pressure-sensitive adhesive and mix evenly to obtain a wet drug mixture.

[0076] Step 4. Coat the wet drug mixture on a release film.

[0077] Step 5. Dry to remove the solvent to obtain a release film / substrate laminate.

[0078] Step 6. Laminate the substrate layer onto the backing layer and perform die-cutting of the composite film to form individual patches.

[0079] Step 7. Fill the packaging container with an inert gas, and seal and package the inert gas, a moisture absorbent and / or an oxygen scavenger, and the cut individual transdermal patches in the container.

[0080] In some embodiments, the solvent in Step 1 includes but is not limited to one or more of toluene, ethanol, isopropanol, dimethylacetamide, dimethyl sulfoxide, and n-heptane, and is preferably toluene, ethanol, isopropanol, n-heptane, or a mixed solvent thereof.

[0081] The present application unexpectedly found that during the preparation of the transdermal patch, the rotigotine-adhesive wet mixture is heated to above room temperature and then coated to produce a substrate layer patch that does not contain rotigotine crystals. On the contrary, if the wet mixture is not heated, crystals are formed in the substrate layer patch.

[0082] In some embodiments, Step 2 includes a step of heating to 35-65 °C to make the drug in a dissolved state. 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.

[0083] 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, 55°C.

[0084] In some embodiments, step 4 is to coat the wet drug mixture on a 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.

[0085] In some embodiments, rotigotine or a pharmaceutically acceptable salt thereof, a pressure-sensitive adhesive, a skin penetration enhancer, and an antioxidant are pre-dried.

[0086] In some embodiments, the moisture absorbent and / or oxygen scavenger are separately packaged in a breathable film; preferably, the moisture absorbent and / or oxygen scavenger packaged in the breathable film are respectively adhered to or placed on the heat-sealing layer inside the packaging container, or the moisture absorbent and / or oxygen scavenger are uniformly incorporated into the heat-sealing layer.

[0087] Another aspect of the present invention provides a use of the aforementioned transdermal drug delivery kit in the preparation of a drug for treating or preventing a disease sensitive to the action of a dopamine receptor agonist.

[0088] In some embodiments, the disease is a disease sensitive to the action of rotigotine.

[0089] In some embodiments, the disease is Parkinson's disease, Parkinson's plus syndrome, depression, restless legs syndrome, pain, and dopaminergic neuron loss.

[0090] Another aspect of the present invention provides a method for treating or preventing a disease sensitive to the action of a dopamine receptor agonist, which comprises administering a therapeutically effective amount of the aforementioned transdermal drug delivery kit to a subject in need thereof.

[0091] In a further embodiment, the rotigotine transdermal drug delivery kit is administered once every 1 day, once every 3 days, or once every 7 days.

[0092] In a further embodiment, the rotigotine transdermal drug delivery kit delivers about 1 mg to about 18 mg of rotigotine or a pharmaceutically acceptable salt thereof to the blood circulation system of the subject every day, preferably about 1 mg to about 12 mg of rotigotine or a pharmaceutically acceptable salt thereof to the blood circulation system of the subject every day.

[0093] This application specifically provides the following embodiments:

[0094] Embodiment 1. A rotigotine transdermal administration kit, which comprises a transdermal patch, and the transdermal patch comprises:

[0095] 1) A backing layer;

[0096] 2) A matrix layer, which contains rotigotine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a stabilizer for inhibiting drug crystallization, an antioxidant, and a pressure-sensitive adhesive; and

[0097] 3) A release liner;

[0098] wherein the transdermal patch is packaged in a packaging container.

[0099] Embodiment 2. The transdermal administration kit according to Embodiment 1, wherein the packaging container is filled with an inert gas; the inert gas is preferably nitrogen; preferably, filling with the inert gas reduces oxygen to less than about 3.0%; more preferably, filling with nitrogen reduces oxygen to about 2.0%, 1.0%, 0.5%, 0.2%, 0.15%, 0.1%, 0.05%, 0.01% or less.

[0100] Embodiment 3. The transdermal administration kit according to Embodiment 1 or 2, wherein the stabilizer for inhibiting drug crystallization contains peroxide; preferably, the stabilizer for inhibiting drug crystallization containing peroxide comprises insoluble cross-linked povidone; further preferably, the insoluble cross-linked povidone is selected from one or more of insoluble cross-linked povidone CL-M, cross-linked povidone CL, cross-linked povidone CL-F, and cross-linked povidone CL-SF.

[0101] Embodiment 4. The transdermal administration kit according to any one of Embodiments 1-3, wherein the stabilizer for inhibiting drug crystallization further comprises soluble povidone on the basis of insoluble cross-linked povidone, and the soluble povidone is preferably one or more of povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, plasdone K29 / 32, and copovidone VA64.

[0102] Embodiment 5. The transdermal administration kit according to any one of Embodiments 1-4, wherein a moisture absorbent that does not contact the matrix layer of the patch is further added to the packaging container.

[0103] Embodiment 6. The transdermal administration kit according to Embodiment 5, wherein the moisture absorbent is selected from one or more of calcium chloride, calcium oxide, barium oxide, calcium sulfate, molecular sieve, sodium sulfate, magnesium sulfate, silicon dioxide, silica gel, potassium hydroxide, potassium carbonate, and phosphorus pentoxide.

[0104] Embodiment 7. The transdermal drug delivery kit according to any one of Embodiments 1-6, wherein an oxygen scavenger that does not contact the patch matrix layer is further added in the packaging container.

[0105] Embodiment 8. The transdermal drug delivery kit according to Embodiment 7, wherein the main components of the oxygen scavenger that does not contact the patch matrix layer are selected from the combinations of iron powder and sodium chloride, ferrous carbonate and metal halides, ascorbate and sodium bicarbonate; preferably the combination of iron powder and sodium chloride.

[0106] Embodiment 9. The transdermal drug delivery kit according to any one of Embodiments 1-8, wherein the desiccant and / or oxygen scavenger are respectively packaged in a breathable membrane; preferably the desiccant and / or oxygen scavenger packaged in the breathable membrane are respectively adhered to or placed on the heat-sealing layer in the packaging container or uniformly included in the heat-sealing layer.

[0107] Embodiment 10. The transdermal drug delivery kit according to any one of Embodiments 1-9, wherein the packaging container has low oxygen permeability and low moisture permeability; preferably a metal tray, a plastic tray, or a packaging bag made of a multi-layer laminate material including a paper layer, an aluminum foil layer, and a heat-sealable inner layer.

[0108] Embodiment 11. The transdermal drug delivery kit according to any one of Embodiments 1-10, wherein the antioxidant is selected from ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, thioglycerol, potassium metabisulfite, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sodium thiosulfate, DL-α-tocopherol; preferably the antioxidant further includes a chelating agent as a co-antioxidant, including one or more of citric acid, tartaric acid, calcium disodium edetate, disodium edetate, and EDTA; the antioxidant is preferably a combination of ascorbyl palmitate, sodium metabisulfite, and DL-α-tocopherol, or a combination of ascorbyl palmitate, sodium metabisulfite, DL-α-tocopherol, and BHT.

[0109] Embodiment 12. The transdermal drug delivery kit according to any one of Embodiments 1-11, wherein relative to the total weight of the matrix layer, the matrix layer comprises the following components:

[0110] 1) The dosage of rotigotine or a pharmaceutically acceptable salt thereof is 3-30%;

[0111] 2) The dosage of a stabilizer that inhibits drug crystallization is 6-40%;

[0112] 3) The dosage of the antioxidant is 0.001%-10%;

[0113] 4) The dosage of the pressure-sensitive adhesive is 30-95%;

[0114] 5) The dosage of the tackifier is 0 - 50%;

[0115] 6) The dosage of the skin penetration enhancer is 0 - 30%;

[0116] 7) The dosage of the cohesion promoting additive is 0 - 20%;

[0117] The total dosage of each component in the matrix layer is 100%.

[0118] Embodiment 13. The transdermal drug delivery kit according to any one of Embodiments 1 - 12, wherein the pressure - sensitive adhesive is selected from one or more of acrylic adhesives, silicone adhesives, acrylic - silicone copolymer adhesives, polybutene adhesives, styrene - isoprene - butene copolymers, and styrene - butadiene - styrene copolymers.

[0119] Embodiment 14. The transdermal drug delivery kit according to any one of Embodiments 12 - 13, wherein the tackifier is selected from silicone oil, light mineral oil, polybutene, triethyl citrate, terpenes, and mixtures thereof.

[0120] Embodiment 15. A method for preparing the transdermal drug delivery kit according to any one of Embodiments 1 - 14, comprising the following steps:

[0121] Step 1. Dissolve the antioxidant in a solvent, dissolve or suspend the stabilizer for inhibiting drug crystallization in the solvent, and mix for 0.1 hour to 24 hours; preferably, the solvent includes, but is not limited to, one or more of toluene, ethanol, isopropanol, dimethylacetamide, dimethyl sulfoxide, and n - heptane, and the solvent is more preferably toluene, ethanol, isopropanol, n - heptane, or a mixed solvent thereof;

[0122] Step 2. Add rotigotine or a pharmaceutically acceptable salt thereof, and mix until rotigotine or a pharmaceutically acceptable salt thereof is dispersed in a non - crystalline state;

[0123] Step 3. Add the pressure - sensitive adhesive and mix evenly to obtain a wet drug mixture;

[0124] Step 4. Coat the wet drug mixture on a release film;

[0125] Step 5. Dry to remove the solvent to obtain a release film / matrix layer laminate;

[0126] Step 6. Laminate the matrix layer onto the backing layer, and perform die - cutting on the composite film to form individual patches;

[0127] Step 7. Fill the packaging container with an inert gas, and seal and package the inert gas, the moisture absorbent and / or the oxygen scavenger, and the cut individual transdermal patches in the container.

[0128] Embodiment 16. The method according to Embodiment 15, wherein Step 2 includes a step of heating to 35-65°C to dissolve the drug; the heating temperature is preferably 45-55°C.

[0129] Embodiment 17. The method according to Embodiment 15 or 16, wherein 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.

[0130] Embodiment 18. The method according to any one of Embodiments 15-17, wherein Step 4 is to coat the wet drug mixture at 35-65°C on a release film; the heating temperature is preferably 45-55°C.

[0131] Embodiment 19. The method according to any one of Embodiments 15-18, wherein the rotigotine or its pharmaceutically acceptable salt, the pressure-sensitive adhesive, the skin penetration enhancer and the antioxidant are pre-dried.

[0132] Embodiment 20. The method according to any one of Embodiments 15-19, wherein the moisture absorbent and / or the oxygen scavenger are separately packaged in a breathable film; preferably, the moisture absorbent and / or the oxygen scavenger packaged in the breathable film are respectively adhered to or placed on the heat-sealing layer in the packaging container or evenly incorporated into the heat-sealing layer.

[0133] Embodiment 21. Use of the transdermal drug delivery kit according to any one of Embodiments 1-20 in the preparation of a drug for treating or preventing a disease sensitive to the action of a dopamine receptor agonist.

[0134] Embodiment 22. The use according to Claim 21, wherein the disease is Parkinson's disease, Parkinson's plus syndrome, depression, restless legs syndrome, pain and dopaminergic neuron loss.

[0135] Embodiment 23. A method for treating or preventing a disease sensitive to the action of a dopamine receptor agonist, which comprises administering to a subject in need a therapeutically effective amount of the transdermal drug delivery kit according to any one of Embodiments 1-20.

[0136] Embodiment 24. The use according to Claim 23, wherein the disease is Parkinson's disease, Parkinson's plus syndrome, depression, restless legs syndrome, pain and dopaminergic neuron loss.

[0137] Definition

[0138] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that, within the scope of reasonable medical judgment, are suitable for contact with a subject (e.g., a human subject) without undue toxicity, irritation, allergic response, etc., have a reasonable benefit / risk ratio, and are effective for their intended use.

[0139] The "pharmaceutically acceptable salts" described in the present invention include inorganic acid addition salts and organic acid addition salts, which can be prepared in situ during the final separation and purification process of the compound, or by reacting the purified compound in free base form (e.g., rotigotine) with a suitable organic or inorganic acid separately and isolating the salt thus formed.

[0140] As used herein, the term "therapeutically effective amount" refers to the amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents a specific disease, disorder, or affliction, (ii) attenuates, ameliorates, or eliminates one or more symptoms of a specific disease, disorder, or affliction, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, disorder, or affliction described herein.

[0141] As used herein, the term "about" refers to plus or minus 10% of the indicated number. For example, "about 10%" can represent a range from 9% to 11%, and "about 1" can represent 0.9 - 1.1.

[0142] As used herein, the term "treatment" refers to a clinical intervention that attempts to alter the natural course of the individual being treated and can be for prophylaxis or during the course of a clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the occurrence or recurrence of a disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating the disease state, and relieving or improving the prognosis.

[0143] 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, which is a white or nearly white powder, odorless and tasteless, has good fluidity, is insoluble in water and various solvents, and is also insoluble in strong acids or strong bases. Non-limiting examples of "insoluble cross-linked povidone" include CL-M, cross-linked povidone CL, cross-linked povidone CL-F, and cross-linked povidone CL-SF.

[0144] As used herein, "iron deoxidizer" is an iron-based deoxidizer, which mainly consists of a combination of iron powder and sodium chloride.

[0145] Pressure-sensitive adhesives include, but are not limited to, acrylic adhesives, silicone adhesives, acrylic-silicone copolymer adhesives, polybutene adhesives, styrene-isoprene-butene copolymers, styrene-butadiene-styrene copolymers, or combinations of two or more adhesives. Examples of acrylic adhesives are Duro- of Henkel Corporation (Bridgewater, New Jersey) 387-2516, Duro- 387-4280, Duro- 387-2287, Duro- 387-2510, Duro- 87-2196, Duro- 387-2051, Duro- 387-2052, Duro- 387-2054, Duro- 87-2194, Duro- 87-235A, Duro- 87-900A, Duro- 87-9301, Duro- 87-4098, GEFVA 788, GEFVA 9073, Duro- 387-2353, Duro- 87-2074, Duro- 87-2852, Duro- 87-2054, -73 80-1196, Duro- 87-2070, Duro- 87-2979, Duro- 87-2888 and Duro- 87-2296. The silicone BIO- of Dupont (Midland, MI) 7-4401, BIO- 7-4402, BIO- 7-4501, BIO- 7-4502, BIO- 7-4601, BIO- 7-4602, SRS7-4502, SRS7-4501, SRS7-4502, SRS7-4602, BIO- 7-4101, BIO- 7-4102, BIO- 7-4103, BIO- 7-4201, BIO- 7-4202, BIO- 7-4203, BIO- 7-4301, BIO- 7-4302, BIO- 7-4302, BIO- 7-6101, BIO- 7-6102, BIO- 7-6301, BIO- -6302. Examples of polybutene adhesives are combinations of two or more low molecular weight polyisobutenes (Oppanol B10, Oppanol B11, Oppanol B12 from BASF), medium molecular weight polyisobutenes (Oppnaol B50, Oppanol B80, Oppnaol N80), and high molecular weight polyisobutenes (Oppanol B100, Oppanol B150, Oppanol N100, Oppanol N150). An example of a styrene-isoprene-butene copolymer is D1161 (Kraton).

[0146] Crystallization inhibitors include polyvinylpyrrolidone or crosslinked polyvinylpyrrolidone or vinylpyrrolidone copolymers, preferably povidone K30, povidone K90, plasdone K29 / 32, copovidone VA64, crosslinked povidone CL-M, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxypropyl betadex, α, β, λ-cyclodextrin, chitosan, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, or carrageenan, or one or more of these.

[0147] As used herein, the term "backing layer" serves as the upper surface of a transdermal patch and, as the main structural element, provides flexibility to the patch. Preferably, the backing layer is substantially impermeable to the pharmaceutical composition for transdermal administration. The backing layer is preferably made of a sheet or film of a flexible elastomeric material. The backing layer is preferably airtight. The backing layer for 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. A non-occlusive backing layer allows the area to breathe (i.e., promotes the transport of water vapor across the skin surface), while an occlusive backing layer reduces the penetration of air / steam. Preferably, the backing layer of the matrix-type transdermal drug delivery kit is occlusive. Preferably, the backing layer comprises a synthetic polymer such as polyolefin, polyester, polyethylene, polyvinylidene chloride, and polyurethane. Preferably, the thickness of the backing layer is from about 0.5 mils 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 / 24 hr to about 100 cc / m / 24 hr, and more preferably, the oxygen transmission rate is from about 70 g / m / 24 hr to about 90 g / m / 24 hr. Preferably, the MVTR is from about 0.1 g / m / 24 hr to about 50 g / m / 24 hr, and more preferably, the MVTR is from about 0.3 g / m / 24 hr to about 30 g / m / 24 hr. In a preferred embodiment, the backing layer is an occlusive polyester film layer about 2.0 mils thick (commercially available, e.g., Scotchpak 9733, Scotchpak 9735, and Scotchpak 9723, 3M Drug Delivery Systems, St. Paul Minn.). Scotchpak 9733 consists of a polyester and a medium-density polyethylene / ethylene vinyl acetate heat-seal layer, and the laminate is translucent, conformable, occlusive, and heat-sealable. More preferably, the backing layer comprises a laminate containing 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 contacting photosensitive rotigotine.

[0148] 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 release liners.

[0149] The present invention has the following advantages and technical effects:

[0150] 1. The inventors of the present invention achieved the stable release of rotigotine by screening to inhibit the crystallization of rotigotine in the transdermal patch formulation.

[0151] 2. The inventors of the present invention reduced the generation of degradation impurities by incorporating an antioxidant combination into the drug-matrix layer.

[0152] 3. The inventors further reduced the generation of degradation impurities by removing air from the packaging container (e.g., sachet) and filling it with an inert gas.

[0153] 4. The inventors reduced the impurities formed by the oxidation pathway in the rotigotine patch by using an antioxidant and a moisture absorbent or a combination of both that do not contact the patch matrix layer. Unexpectedly, the moisture absorbent reduced the generation of oxidative impurities. Further adding an oxygen scavenger that does not contact the patch on the basis of removing air and filling with an inert gas and the moisture absorbent does not result in a decrease in stability.

[0154] 5. The inventors found that during the preparation of the transdermal patch, the rotigotine - adhesive wet mixture was heated above room temperature and then coated to produce a matrix layer patch that does not contain rotigotine crystals.

[0155] 6. The inventors reduced impurities by pre - drying the rotigotine API and excipients before mixing.

[0156] Therefore, the present invention obtains a stable rotigotine transdermal delivery kit, which can be stored for a long time under conventional conditions, the rotigotine dispersed in the patch matrix does not crystallize, and the related substances are maintained at an extremely low level. Detailed Description

[0157] To make the objectives, 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. Apparently, the described embodiments are a module embodiment of the present invention, rather than all embodiments. The elements and features described in one embodiment of the present invention can be combined with the elements and features shown in one or more other embodiments. It should be noted that for the sake of clarity, the representation and description of components and processes that are irrelevant to the present invention and known to those of ordinary skill in the art are omitted. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0158] Abbreviations:

[0159] PVP K90 = Polyvinylpyrrolidone K90, Crosslinked Polyvinylpyrrolidone = Crosslinked Polyvinylpyrrolidone CL-M, Ascorbyl Palmitate, Sodium Metasulfite is Sodium Pyrosulfite, BHT is 2,6-Di-tert-butyl-p-cresol, Bio-PSA 7-4202 is a pressure-sensitive adhesive, Bio-PSA 7-4302 is a pressure-sensitive adhesive, Bio-PSA SRS7-4502 is a pressure-sensitive adhesive, Oppanol B12 SFN is a polyisobutene adhesive, Oppanol N100 is a polyisobutene adhesive.

[0160] Comparative Example 1

[0161] Weigh each component according to Table 1. Dissolve soluble polyvinylpyrrolidone K90 and antioxidants α-dl-tocopherol, ascorbyl palmitate and sodium pyrosulfite in ethanol. After heating the mixture to 50 °C, add rotigotine until it dissolves; then add silicone adhesives Bio-PSA 7-4302 and Bio-PSA 7-4202 and mix evenly. Coat the mixture on a release film and dry it at 40 °C for 4 minutes and at 85 °C for 4 minutes to remove the solvent. In this comparative example, the formulated patch was packaged in an aluminum foil bag without nitrogen and desiccant. As shown in Table 1, after storing at 40 °C for 6 months, the contents of EP impurity B, EP impurity C and EP impurity K in Comparative Example 1 were high.

[0162] Comparative Example 2

[0163] Weigh each component according to Table 1 and prepare the transdermal patch of Comparative Example 2 using the same method as in Comparative Example 1. In Comparative Example 2, the formulated patch was packaged in an aluminum foil bag without nitrogen and desiccant. As shown in Table 1, after storing at 40 °C for 6 months, the contents of EP impurity B, EP impurity C and EP impurity K in Comparative Example 2 were relatively high.

[0164] Comparative Example 3

[0165] Weigh each component according to the following weight ratios: 3.33% PVP K90, 0.0200% ascorbyl palmitate, 0.0009% sodium metabisulfite, 0.0200% DL-α-tocopherol, 7.5% rotigotine, 13.3694% Bio-PSA 7-4302, 75.7597% Bio-PSA 7-4202. Dissolve soluble polyvinylpyrrolidone K90 and antioxidants α-dl-tocopherol, ascorbyl palmitate and sodium metabisulfite in ethanol. After heating the mixture to 50 °C, add rotigotine until it dissolves; then add room-temperature silicone adhesives Bio-PSA 7-4302 and Bio-PSA 7-4202 and mix evenly. Coating the mixture on a release film and drying it at 40 °C for 4 minutes and at 85 °C for 4 minutes to remove the solvent. In this comparative example, the formulated patch was packaged in an aluminum foil bag without nitrogen or desiccant. After storing at 40 °C for 6 months, Comparative Example 3 was similar to Comparative Examples 1-2, and the contents of EP impurity B, EP impurity C and EP impurity K were relatively high.

[0166] After storing Comparative Examples 1-3 at room temperature, 40 °C or 60 °C for a period of time, crystallization of rotigotine will be observed.

[0167] Comparative Example 4

[0168] Weigh each component according to Table 1. Dissolve antioxidants α-dl-tocopherol, ascorbyl palmitate and sodium metabisulfite in ethanol, and further mix for 24 hours after adding insoluble crospovidone. After heating the mixture to 50 °C, add rotigotine until it dissolves; add room-temperature silicone adhesives Bio-PSA 7-4302 and Bio-PSA 7-4202 and mix evenly. Coating the mixture on a release film and drying it at 40 °C for 4 minutes and at 85 °C for 4 minutes to remove the solvent. In this comparative example, the formulated patch was packaged in an aluminum foil bag without nitrogen or desiccant.

[0169] As shown in Table 1, due to the high content of crospovidone in the formulation, compared with Comparative Examples 1, 2 and 3, the contents of EP impurity B, EP impurity C, EP impurity E and EP impurity K in Comparative Example 4 were relatively high. The stability data of Comparative Examples 1-4 showed that, compared with PVP K90, the use of crospovidone accelerated the degradation of rotigotine in the patch formulation and reduced the stability of the patch formulation.

[0170] Examples 1-2

[0171] Weigh each component according to Table 1. Prepare the formulation patches of Examples 1-2 by a method similar to that of Comparative Example 3. Reduce the oxygen to 0.2% under nitrogen filling for the formulation patches of Examples 1-2 and package them in an aluminum foil bag. Compared with Comparative Examples 1-3, after storage at 40 °C for 6 months, the contents of EP impurity B, EP impurity C, and EP impurity K in the formulation patches of Examples 1-2 are significantly lower. The results show that on the basis of using antioxidant components in the formulation patch, using nitrogen filling packaging can further inhibit the degradation of rotigotine.

[0172] Stability data of Comparative Examples 1-4 and Examples 1-2 in Table 1

[0173]

[0174]

[0175] Comparative Example 5 and Examples 3-6

[0176] Weigh each component according to Table 1. Dissolve soluble polyvinylpyrrolidone K90 and antioxidants α-dl-tocopherol, ascorbyl palmitate, and sodium metabisulfite in ethanol, add cross-linked polyvinylpyrrolidone and further mix for 24 hours. Heat the mixture to 50 °C, add rotigotine until it dissolves, then add room-temperature silicone adhesives Bio-PSA 7-4302 and Bio-PSA 7-4202 and mix evenly. Coat the suspension on a release film and dry it at 40 °C for 4 minutes and at 85 °C for 4 minutes to remove the solvent. Package the formulation patches using different packaging methods, and place them at 60 °C for 5 days to examine the related substances of Comparative Example 5 and Examples 3-6. The experimental conclusions are summarized in Table 2.

[0177] The formulation patch of Comparative Example 5 is only packaged in an aluminum foil bag.

[0178] The formulation patch of Example 3 reduces the oxygen to 0.2% under nitrogen filling and is packaged in an aluminum foil bag. Compared with Comparative Example 5, the contents of EP impurity B, EP impurity C, and EP impurity K in Example 3 are reduced.

[0179] The formulation patch of Example 4 places an oxygen scavenger iron that does not contact the patch in the packaging bag, reduces the oxygen to 0.2% under nitrogen filling, and packages the patch and the oxygen scavenger iron in an aluminum foil bag. Compared with Example 3, there is no difference in the impurity content for Example 4. Further adding an oxygen scavenger iron on the basis of nitrogen filling packaging will not lead to a decrease in stability.

[0180] The formulation patch of Example 5 places a moisture-absorbing film bag containing hygroscopic calcium oxide in the packaging bag, reduces the oxygen to 0.2% under nitrogen filling, and packages the patch and the moisture-absorbing film bag in an aluminum foil bag. Further adding a moisture-absorbing film bag on the basis of nitrogen filling packaging can inhibit the generation of some impurities.

[0181] Example 6 Preparation Patch A moisture-absorbing film bag containing moisture-absorbing calcium oxide and an oxygen scavenger iron are placed in a packaging bag. Under nitrogen filling, the oxygen is reduced to 0.2%, and the patch, the moisture-absorbing film bag, and the oxygen scavenger iron are packaged into an aluminum foil bag. Further adding the moisture-absorbing film bag and the oxygen scavenger iron on the basis of nitrogen filling packaging will not cause a decrease in stability.

[0182] Table 2 data shows that there is little difference in the content of degradation impurities among Examples 3, 4, 5, and 6. In the transdermal patch formulations using the crystallization inhibitor PVP K90 and cross-linked PVP simultaneously, if the amount of cross-linked PVP used is not large, using an aluminum foil package filled with N2 can inhibit the degradation of rotigotine. Further increasing the moisture absorbent, the oxygen scavenger iron, and the combination of the moisture absorbent and the oxygen scavenger iron on the basis of N2 filling will not cause a decrease in stability.

[0183] Table 2. Stability data of Comparative Example 5 and Examples 3-6

[0184]

[0185]

[0186] Comparative Examples 6-10 and Examples 7-9

[0187] Weigh each composition component according to Table 3 and prepare the formulation. Dissolve the antioxidants ascorbyl palmitate, sodium metabisulfite, and α-dl-tocopherol in isopropanol at 50°C; add insoluble cross-linked polyvinylpyrrolidone and mix at room temperature for 24 hours. Heat the suspension to 50°C, add rotigotine until completely dissolved. Add and mix the light mineral oil heated to 50°C and the solutions of polyisobutene adhesives Oppanol B12 and Oppanol N100 in n-heptane. Keep the suspension at 50°C, coat it on a release film, and dry it at 40°C for 4 min and at 85°C for 4 min to remove the solvent.

[0188] In Comparative Examples 6-10 and Examples 7-9, only cross-linked polyvinylpyrrolidone is used as the crystallization inhibitor of rotigotine.

[0189] Neither nitrogen nor a moisture absorbent is used in the aluminum foil bags of Comparative Examples 6-10. As shown in Table 3, the contents of EP impurity B, EP impurity C, EP impurity E, and EP impurity K in Comparative Examples 6-10 increase significantly after being stored at 40°C for 3 months.

[0190] Examples 7 - 9 The patch preparations reduce oxygen to 0.2% under nitrogen filling and are packaged in aluminum foil bags. As shown in Table 3, after being stored at 60°C, 40°C, and room temperature for a period of time, Examples 7 - 9 have lower contents of EP impurity B, EP impurity C, EP impurity E, and EP impurity K compared to Comparative Examples 6 - 10. The results indicate that nitrogen filling packaging can inhibit the degradation of rotigotine in the formulation using only cross-linked povidone.

[0191] Table 3. Stability data of Comparative Examples 6 - 9 and Examples 7 - 9

[0192]

[0193]

[0194]

[0195] Examples 10 - 12

[0196] Weigh each composition component according to Table 4 and prepare the formulation. Dissolve the antioxidants ascorbyl palmitate, sodium metabisulfite, DL-α-tocopherol, and BHT in isopropanol at 50°C; add insoluble cross-linked povidone and mix at room temperature for 24 hours. Heat the suspension to 50°C, add rotigotine until completely dissolved. Add and mix the solution of light mineral oil, polyisobutene binder Oppanol B12, and Oppanol N100 in n-heptane, which is heated to 50°C. Keep the suspension at 50°C, coat it on the release film, and dry it at 40°C for 4 min and at 85°C for 4 min to remove the solvent.

[0197] The patch of Example 10 reduces oxygen to 0.2% under nitrogen filling and is packaged in an aluminum foil bag. After being stored at 60°C, 40°C, and room temperature for a period of time, the contents of EP impurity B, EP impurity C, and EP impurity K remain at a low level.

[0198] In Example 11, a moisture-absorbing film bag containing silica gel is placed in the packaging bag. Oxygen is reduced to 0.2% under nitrogen filling, and the patch and the silica gel moisture-absorbing film bag are packaged in an aluminum foil bag. Further adding a silica gel moisture-absorbing film bag on the basis of nitrogen filling packaging can further inhibit the generation of impurities.

[0199] In Example 12, a moisture-absorbing film bag containing hygroscopic calcium chloride is placed in the packaging bag. Oxygen is reduced to 0.2% under nitrogen filling, and the patch and the moisture-absorbing film bag are packaged in an aluminum foil bag. Adding a moisture-absorbing film bag containing hygroscopic calcium chloride on the basis of nitrogen filling packaging can further inhibit the generation of impurities.

[0200] Compared with Example 10, Examples 11-12 using a moisture absorbent further suppressed the generation of degradation impurities, especially oxidation degradation impurities and their secondary degradation impurities.

[0201] Table 4. Stability data of Examples 10-12

[0202]

[0203]

[0204] Comparative Example 11 and Examples 13-16

[0205] Weigh each component according to Table 5. Dissolve the antioxidants ascorbyl palmitate, sodium metabisulfite, and DL-α-tocopherol in isopropanol at 50 °C; add insoluble crospovidone and mix at room temperature for 24 hours. Heat the suspension to 50 °C, add rotigotine until completely dissolved. Add and mix a solution of light mineral oil, polyisobutene binder Oppanol B12 and Oppanol N100 in n-heptane heated to 50 °C. Keep the suspension at 50 °C, coat it on a release film and dry it at 40 °C for 4 min and at 85 °C for 4 min to remove the solvent.

[0206] The formulated patches were packaged using different packaging methods and placed at 60 °C for 5 days to examine the related substances of Comparative Example 11 and Examples 13-16. The experimental conclusions are summarized in Table 5.

[0207] The formulated patch of Comparative Example 11 was packaged only using an aluminum foil bag.

[0208] The formulated patch of Example 13 reduced the oxygen to 0.2% under nitrogen filling and was packaged into an aluminum foil bag. Compared with Comparative Example 11, the contents of EP impurity B, EP impurity C, and EP impurity K in Example 13 decreased.

[0209] The formulated patch of Example 14 placed an oxygen scavenger iron in the packaging bag, reduced the oxygen to 0.2% under nitrogen filling, and packaged the patch and the oxygen scavenger iron into an aluminum foil bag. There was no difference in the impurity content between Example 14 and Example 13. Further adding an oxygen scavenger iron on the basis of nitrogen filling packaging did not lead to a decrease in stability.

[0210] The formulated patch of Example 15 placed a moisture-absorbing film bag containing hygroscopic calcium oxide in the packaging bag, reduced the oxygen to 0.2% under nitrogen filling, and packaged the patch and the moisture-absorbing film bag into an aluminum foil bag. Further adding a moisture-absorbing film bag on the basis of nitrogen filling packaging could inhibit the generation of four impurities.

[0211] Example 16 Preparation Patch A moisture-absorbing film bag containing hygroscopic calcium oxide and an oxygen scavenger iron were placed in a packaging bag. Under nitrogen filling, the oxygen was reduced to 0.2%, and the patch, the moisture-absorbing film bag, and the oxygen scavenger iron were packaged into an aluminum foil bag. The relevant impurity levels of Example 16 and Example 15 were close.

[0212] It shows that further adding a moisture-absorbing film bag and an oxygen scavenger iron on the basis of nitrogen-filled packaging will not lead to a decrease in stability.

[0213] The data in Table 5 show that in a transdermal patch formulation using only cross-linked PVP as a rotigotine crystallization inhibitor, using an aluminum foil package filled with N2 can inhibit the degradation of rotigotine. If the amount of cross-linked PVP is large, adding a moisture absorbent on the basis of N2 filling can further inhibit the degradation of rotigotine. Further adding an oxygen scavenger iron in the packaging will not lead to a decrease in stability.

[0214] Table 5. Stability data of Comparative Example 11 and Examples 13 - 16

[0215]

[0216]

Claims

1. A rotigotine transdermal delivery kit, which comprises a transdermal patch, and the transdermal patch comprises: 1) A backing layer; 2) A matrix layer, which contains rotigotine or a pharmaceutically acceptable salt thereof dispersed in the matrix layer in an amorphous state, a stabilizer for inhibiting drug crystallization, an antioxidant, and a pressure-sensitive adhesive; and 3) A release liner; wherein the transdermal patch is packaged in a packaging container.

2. The transdermal delivery kit according to claim 1, wherein the packaging container is filled with an inert gas; the inert gas is preferably nitrogen; preferably, filling with the inert gas reduces oxygen to less than about 3.0%; more preferably, filling with nitrogen reduces oxygen to about 2.0%, 1.0%, 0.5%, 0.2%, 0.15%, 0.1%, 0.05%, 0.01% or less.

3. The transdermal delivery kit according to claim 1 or 2, wherein the stabilizer for inhibiting drug crystallization contains peroxide; preferably, the stabilizer for inhibiting drug crystallization containing peroxide comprises insoluble cross-linked povidone; further preferably, the insoluble cross-linked povidone is selected from one or more of insoluble cross-linked povidone CL-M, cross-linked povidone CL, cross-linked povidone CL-F, and cross-linked povidone CL-SF.

4. The transdermal delivery kit according to any one of claims 1-3, wherein the stabilizer for inhibiting drug crystallization further comprises soluble povidone on the basis of insoluble cross-linked povidone, and the soluble povidone is preferably one or more of povidone K30, povidone K90, povidone K12, povidone K17, povidone K25, plasdone K29 / 32, and copovidone VA64.

5. The transdermal delivery kit according to any one of claims 1-4, wherein a moisture absorbent that does not contact the matrix layer of the patch is further added to the packaging container.

6. The transdermal delivery kit according to claim 5, wherein the moisture absorbent is selected from one or more of calcium chloride, calcium oxide, barium oxide, calcium sulfate, molecular sieve, sodium sulfate, magnesium sulfate, silicon dioxide, silica gel, potassium hydroxide, potassium carbonate, and phosphorus pentoxide.

7. The transdermal delivery kit according to any one of claims 1-6, wherein an oxygen scavenger that does not contact the matrix layer of the patch is further added to the packaging container.

8. The transdermal delivery kit according to claim 7, wherein the main components of the oxygen scavenger that does not contact the matrix layer of the patch are selected from the combination of iron powder and sodium chloride, ferrous carbonate and metal halide, and ascorbate and sodium bicarbonate; preferably the combination of iron powder and sodium chloride.

9. The transdermal delivery kit according to any one of claims 1-8, wherein the moisture absorbent and / or the oxygen scavenger are respectively packaged in a breathable film; preferably, the moisture absorbent and / or the oxygen scavenger packaged in the breathable film are respectively adhered to or placed on the heat-sealing layer in the packaging container or uniformly included in the heat-sealing layer.

10. The transdermal drug delivery kit according to any one of claims 1-9, wherein the packaging container has low oxygen permeability and low moisture permeability; preferably a metal tray, a plastic tray, or a packaging bag made of a multi-layer laminate material comprising a paper layer, an aluminum foil layer, and a heat-sealable inner layer.

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