Rasagiline mesylate-containing transdermal patch and method for preparing same

Abstract

The present invention provides a rasagiline mesylate-containing transdermal patch and a preparation method thereof, which further comprises one or more release promoters selected from acetylpropionic acid, octanoic acid, and undecenoic acid, and which is formed by forming a hydrogen bond complex through the cooperative action of rasagiline mesylate with cross-linked polyvidone and a crystallization inhibitor, thereby causing rasagiline mesylate to exist in an amorphous state in a drug carrier and preventing it from existing in an unstable form as a free base.

Description

[Technical Field]

[0001] The present invention relates to the field of transdermal administration of drug formulations, and in particular to a rasagiline mesylate-containing transdermal patch and a method for preparing the same. [Background technology]

[0002] Rasagiline is an irreversible, selective monoamine oxidase B (MAO-B) inhibitor used to treat Parkinson's disease (PD), a degenerative central nervous system disorder. Oral formulations of this drug are already commercially available in Europe, available in both 0.5 mg / d and 1 mg / d doses. Rasagiline, an irreversible monoamine oxidase inhibitor, is highly effective and safe, with no serious adverse reactions observed after oral administration of 20 mg / d for two weeks. Parkinson's patients experience an on-off phenomenon, which limits their movement during the off-phase and makes it difficult for them to move around, making oral administration difficult. Transdermal administration can significantly improve patient compliance. Meanwhile, the bioavailability of oral formulations is relatively low (only 36%). Transdermal administration, which directly enters the bloodstream, significantly improves drug bioavailability. At present, in the treatment of Parkinson's disease, rotigotine transdermal patches have been marketed, and compared with oral administration, rotigotine transdermal patches have the clinical advantage of improving patient compliance.The development of rasagiline transdermal patches can facilitate administration to Parkinson's patients, improve patient compliance and drug bioavailability.According to the literature, under weakly basic conditions, whether rasagiline free base is supported on polyacrylic acid pressure-sensitive adhesive, silicone pressure-sensitive adhesive, or polyvinyl alcohol, the active ingredient content decreases very quickly, and even the entire product is decomposed, making it very unstable.However, as a mesylate drug of rasagiline, whether rasagiline mesylate is supported on polyacrylic acid pressure-sensitive adhesive, silicone pressure-sensitive adhesive, or polyvinyl alcohol, the active ingredient content does not change, so rasagiline mesylate is very suitable for the formulation of transdermal patches.

[0003] Transdermal Drug Delivery Systems (TDDS) (also known as Transdermal Therapeutic Systems (TTS)) are a new drug delivery method for the treatment or prevention of diseases by allowing drugs to enter the blood circulation through the skin and reach effective blood drug concentrations. Transdermal drug delivery systems offer four main advantages: (1) they avoid gastrointestinal irritation and drug degradation, while also avoiding the first-pass effect in the liver, thereby improving drug bioavailability; (2) they provide stable and sustained drug release, reducing side effects caused by peak-valley fluctuations; (3) they eliminate the need for frequent administration, improving patient compliance (for the elderly, infants, and critically ill patients); and (4) they are convenient and flexible, allowing for immediate discontinuation of administration if side effects are detected.

[0004] In summary, rasagiline mesylate can be formulated into a transdermal patch for dermal administration, which has many advantages and provides more options for patients.

[0005] Currently, there are several transdermal administration methods for rasagiline: (1) Spray transdermal absorption is characterized by the use of a skin penetration enhancer with a unique composition (US2004013620). However, the transdermal absorption effect is not ideal.

[0006] (2) Transdermal patches. The method disclosed in Chinese Patent CN101032474B, "Rasagiline transdermal patch for treating or preventing nervous system diseases and its preparation method," can achieve good transdermal penetration, but the drug stability is poor. In this patent, rasagiline exists mainly in the form of a free base at high pH, ​​and the R-NH-C≡CH bond between its secondary amine group and the alkynyl group linked to it is easily cleaved, causing decomposition. Therefore, rasagiline is difficult to maintain long-term stability in a basic substrate environment, and the instability is particularly pronounced when it is in the free base form, resulting in poor drug stability and unsuitable for long-term storage.

[0007] The transdermal administration of rasagiline has many advantages. The drawbacks of existing transdermal administration technologies for rasagiline are: (1) the transdermal absorption effect of spray transdermal absorption (US2004013620) is not ideal, and (2) the transdermal patch system has a high pH, ​​and rasagiline exists mainly in the form of free base, which is very unstable and difficult to store for a long time. Summary of the Invention

[0008] The present invention provides a transdermal patch containing rasagiline mesylate for the first time, with the aim of addressing the problems of existing transdermal patches, such as poor absorption, instability, drug precipitation, and difficulty in long-term storage. The present invention designs a technical solution for supporting rasagiline mesylate in a water-insoluble carrier, and provides a transdermal patch containing rasagiline mesylate for the first time, comprising a backing layer, a matrix layer, and a protective layer.

[0009] In one embodiment, the matrix layer (referred to as a matrix mixture in this patent application when not applied) contains the following components in weight percent contents: 0.5-8.0% rasagiline mesylate, 40-80% adhesive, 3-25% cross-linked polyvidone, 1-5% crystallization inhibitor, 1-15% permeation enhancer, 1-10% plasticizer, and 0.001-0.5% antioxidant, with the amount of adhesive adjusted so that the mass ratio of rasagiline mesylate to cross-linked polyvidone is 1:5-1:15, ultimately achieving 100% mass percent. Preferably, the rasagiline mesylate content is 0.5-5.0%.

[0010] Solution 2 is characterized in that the matrix layer (referred to as matrix mixture in this patent application when not applied) contains the following mass percent contents of components: 0.5-5.0% rasagiline mesylate, 40-80% adhesive, 3-25% cross-linked polyvidone, 0.1-5.0% release enhancer, 1-15% penetration enhancer, 0.5-10% plasticizer, and 0.001-0.5% antioxidant, and the mass ratio of rasagiline mesylate to cross-linked polyvidone is 1:5-1:15, and the amount of adhesive is adjusted to finally adjust to 100% mass percent.

[0011] The beneficial effects of adopting the above technical proposal are as follows: The adhesives selected for current TDDS delivery systems are mainly acrylate-based, organic polysiloxane-based, hot-melt adhesive-based, etc., and all of these adhesives are organic solvent-based dissolution systems, mainly used in transdermal patches for lipophilic drugs, and have the problem of incompatibility between rasagiline mesylate and solvent-based adhesives. The present invention creatively uses cross-linked polyvidone, a drug carrier commonly used to carry lipophilic or water-insoluble drugs, to carry the water-soluble drug rasagiline mesylate, and forms a hydrogen bond complex with the drug carrier and crystallization inhibitor, allowing rasagiline mesylate to exist stably in an amorphous state in the drug carrier, so that the prepared patch is free from crystallization, and rasagiline exists in the form of a salt, preventing the formulation from becoming unstable. This type of combination is the first to be described in transdermal patches.

[0012] In particular, the inventors have found through experimental research that when the drug loading is low (<0.5%), rasagiline mesylate does not precipitate large amounts of crystals when combined without the addition of PVPP. This is because the system has a certain degree of solubility for the drug. However, when the rasagiline mesylate content exceeds 0.50%, large amounts of crystals precipitate. Considering the drug's drug ... Through experimental investigation, it was found that the maximum drug loading of the system was less than 5.0% by mass of rasagiline mesylate, and if it was too much, the process would be difficult to implement. Further experiments showed that when the mass ratio of rasagiline mesylate to cross-linked polyvidone was 1:5 to 1:15, the system had relatively good druggability.

[0013] Therefore, the formulation of the rasagiline mesylate-containing transdermal patch proposed by the present invention can prepare a patch with a high drug loading, a drug that does not precipitate even after long-term storage, and meets drug drugability. Tests have shown that when the thickness of the matrix layer of the final prepared patch is appropriate, the content of the active drug per unit area is 0.058-0.565 mg / cm2 in terms of rasagiline free base. 2 It was realized that the salt-type drug can be carried in a relatively high concentration in the organic solvent pressure-sensitive adhesive system without crystallization.

[0014] Furthermore, the formulation of the present invention does not use inorganic salts, inorganic bases, or organic bases, thereby overcoming the problems of skin discomfort, redness, and swelling that inevitably occur when applying a patch to the patient's outer epidermis, which is caused by using inorganic salts, inorganic bases, or organic bases to adjust the pH value in the technical solution of CN101032474B (CN101032474B emphasizes adjusting the pH to an appropriate range, but adding inorganic salts, inorganic bases, or organic bases inevitably irritates the skin and causes discomfort).

[0015] Drugs can be released and delivered accurately, stably, and sustainably without the use of a release-controlling membrane. The transdermal effect is ideal, with a 24-hour cumulative permeation rate of 20-100 μg / cm 2 can be reached.

[0016] It has an excellent user experience, and the drug carrier is insoluble in water and ethanol and exists in the form of particles in the formulation, which prevents the sticky feeling and adhesive residue problems caused by incorporating a high proportion of polymer crystallization inhibitor, which affects the comfort of use.

[0017] In Plan 1 and Plan 2, Preferably, the adhesive is an acrylate pressure sensitive adhesive.

[0018] Preferably, the acrylate pressure sensitive adhesive is one or a combination of several selected from DURO-TAK 387-2516, DURO-TAK 387-2052, DORO-TAK 87-4098, and DORO-TAK 387-2287.

[0019] Preferably, the crystallization inhibitor is at least one substance selected from polyvidone K90, polyvidone K30, polyvidone K25, polyvidone K17, polyvidone K12, and copovidone VA64.

[0020] Preferably, the crystallization inhibitor is one or a combination of several selected from polyvidone K25, polyvidone K17, polyvidone K12 and copovidone VA64.

[0021] Preferably, the penetration enhancer is at least one substance selected from propylene glycol monocaprylate, polyglycerol fatty acid ester, glycerin monooleate, glycerin monolinoleate (glycerin 1-linolate), glycerin monostearate, Span 80, and Span 60.

[0022] Preferably, the penetration enhancer is selected from propylene glycol monocaprylate or polyglycerol fatty acid esters.

[0023] Preferably, the plasticizer is one or a combination of several selected from the group consisting of triethyl citrate, glycerin triacetate, and dibutyl phthalate.

[0024] Preferably, the plasticizer is triethyl citrate. Preferably, the antioxidant is one or a combination of several selected from vitamin E (tocopherol), tocopherol acetate, tocopherol succinate, tocopherol nicotinate, tocopherol palmitate, tocopherol linoleate, and tocopherol phosphate.

[0025] Preferably, the antioxidant is selected from vitamin E (tocopherol). Preferably, the backing layer is SCOTCHPAK TM 9738, SCOTCHPAK TM 9730, SCOTCHPAK TM It is one of the types selected from 1109.

[0026] Preferably, the protective layer is made of SCOTCHPAK TM 1022 or SCOTCHPAK TMIt is one of the types selected from 2504.

[0027] In Plan 1, Preferably, the matrix layer further comprises a release promoter component in a mass percent content of 0.1 to 5.0%.

[0028] Preferably, the mass ratio of rasagiline mesylate to the crystallization inhibitor is 3:1 to 3:5. Preferably, the mass ratio of the plasticizer to the penetration enhancer is 1:1 to 1:5.

[0029] In Plan 2, Preferably, the substrate layer further comprises a crystallization inhibitor component with a mass percent content of 1-5%.

[0030] Preferably, the mass ratio of the release enhancer to rasagiline mesylate is 1:1 to 1:4.

[0031] Preferably, the mass ratio of the plasticizer to the penetration enhancer is 1:1 to 1:10.

[0032] Preferably, the mass ratio of the release enhancer to the penetration enhancer is 1:1 to 1:15.

[0033] In Plan 1 and Plan 2, The release promoter is one or a combination of several selected from acetylpropionic acid, octanoic acid, and undecenoic acid, and is preferably acetylpropionic acid.

[0034] Preferably, the backing layer is made of SCOTCHPAK. TM 9738, SCOTCHPAK TM 9730, SCOTCHPAK TM 1109, and the protective layer is SCOTCHPAK TM 1022, SCOTCHPAK TM 2504, 75E-0010BD.

[0035] Method one, The present invention provides a tape 1 for preparing a drug-containing adhesive layer (substrate layer; in this patent application, when not coated, it is referred to as a substrate mixture) by dissolving 0.5-8% rasagiline mesylate (preferably 0.5-5.0%), 1-5% crystallization inhibitor, 1-15% penetration enhancer, 1-10% plasticizer, and 0.001-0.5% antioxidant in a solvent and mixing and stirring until the solids are completely dissolved and a uniform solution is obtained; adding 3-25% cross-linked polyvidone to the uniform solution and premixing until the solution is sufficiently swollen, followed by homogenization to obtain a white milky liquid; adding 40-80% adhesive to the white milky liquid and mixing and stirring until uniform, to obtain an intermediate solution;

[0036] a tape 2 in which the intermediate solution is applied to a release film (protective layer) to obtain a wet film having a thickness of 100 to 500 μm, and then dried to obtain a dry substrate, and the solvent is removed by coating and drying to obtain a dry film having a thickness of 20 to 250 μm;

[0037] A laminated composite and cutting tape 3 is included, which laminates the backing film (backing layer) with the dry substrate to form a composite, and then cuts it into patches.

[0038] The present invention further provides a method for preparing a transdermal patch of rasagiline mesylate, characterized in that in tape 1, the mass ratio of rasagiline mesylate to cross-linked polyvidone is 1:5 to 1:15, and the amount of adhesive is adjusted so that the final mass percentage is 100%.

[0039] Method two, The present invention provides a drug-containing matrix layer (referred to as a matrix mixture in this patent application when not coated) prepared by dissolving 0.5-5.0% rasagiline mesylate, 0.1-5.0% release enhancer, 1-15% permeation enhancer, 0.5-10% plasticizer, and 0.001-0.5% antioxidant in a solvent and mixing and stirring until the solids are completely dissolved to obtain a uniform solution; adding 3-25% cross-linked polyvidone to the uniform solution and premixing to allow the solution to swell sufficiently, followed by homogenization to obtain a white milky liquid; adding 40-80% adhesive to the white milky liquid and mixing and stirring until uniform to obtain an intermediate solution;

[0040] a tape 2 for removing the solvent by coating and drying the intermediate solution onto the protective layer to obtain a wet film having a thickness of 100 to 500 μm, and then drying the intermediate solution to obtain a dry substrate having a dry film having a thickness of 20 to 250 μm;

[0041] a laminate composite and cutting tape 3 for laminating the backing layer with the dry substrate to composite it, and cutting it into patches;

[0042] The present invention further provides a method for preparing a transdermal patch of rasagiline mesylate, characterized in that in tape 1, the mass ratio of rasagiline mesylate to cross-linked polyvidone is 1:5 to 1:15, and the amount of adhesive is adjusted so that the final mass percentage is 100%.

[0043] The beneficial effects of adopting the above technical proposals are as follows:

[0044] The rasagiline mesylate, the drug carrier cross-linked polyvidone, and the crystallization inhibitor act synergistically to form a hydrogen bond complex, allowing the rasagiline mesylate to exist in an amorphous state in the drug carrier. The prepared patch is free from crystallization, and rasagiline exists in the form of a salt, preventing instability of the formulation.

[0045] In Method 1 and Method 2, Preferably, the solvent in the tape 1 is one or a combination of absolute ethanol or isopropanol, and absolute ethanol is more preferred.

[0046] Preferably, the solvent in tape 1 is selected from absolute ethanol. Preferably, the drying in step 2 is performed in a three-stage drying method, with the first stage being at 20 to 30°C for 2 to 10 minutes (preferably at 20 to 25°C for 2 to 10 minutes), the second stage being at 45 to 65°C for 2 to 10 minutes, and the third stage being at 65 to 85°C for 2 to 10 minutes.

[0047] In method 1, Preferably, the matrix layer further comprises a release promoter component in a mass percent content of 0.1 to 5.0%.

[0048] Preferably, the mass ratio of rasagiline mesylate to the crystallization inhibitor is 3:1 to 3:5. Preferably, the mass ratio of the plasticizer to the penetration enhancer is 1:1 to 1:5.

[0049] In method 2, The substrate layer further comprises a crystallization inhibitor component with a mass percent content of 1-5%.

[0050] Preferably, the mass ratio of the release enhancer to rasagiline mesylate is 1:1 to 1:4.

[0051] Preferably, the mass ratio of the plasticizer to the penetration enhancer is 1:1 to 1:10.

[0052] Preferably, the mass ratio of the release enhancer to the penetration enhancer is 1:1 to 1:15.

[0053] In Method 1 and Method 2, it is preferable that the area to be used after cutting is 3 cm 2 ~30cm 2 is.

[0054] In particular, unless otherwise specified, all numerical ranges in the specification of this application have an error of ±10% due to unavoidable errors in the measurement results of measuring instruments. [Brief explanation of the drawings]

[0055] [Figure 1] 1 is a cross-sectional view of a transdermal patch according to the present invention. [Figure 2] 1 is a plot of the Qt relationship for the formulations of Examples 3 to 7 of the present invention. [Figure 3] 1 is a plot of the Qt relationship for the formulations of Examples 8 and 9 of the present invention. [Figure 4] 1 is a polarizing microscope photograph of the patches prepared according to the formulations of Examples 1' to 3' of the present invention after placement. DETAILED DESCRIPTION OF THE INVENTION

[0056] The preferred embodiments in the following description are merely examples, and other obvious modifications may occur to those skilled in the art. The basic principles of the present invention defined in the following description may be applied to other implementations, modifications, improvements, equivalents, and other technical solutions that do not depart from the spirit and scope of the present invention.

[0057] In the following description, Examples 1-2 compare formulations with and without PVPP (cross-linked polyvidone) to demonstrate the ability of PVPP to carry the water-soluble drug rasagiline mesylate.

[0058] Examples 3 to 7 are IVPTs (IVPT: In Vitro Permeation Testing) used to screen formulations containing no penetration enhancer and formulations containing penetration enhancers with HLB values ​​of 1 to 5 (HLB: Hydrophile Lipophilic Balance). These IVPTs further explain the necessity of using penetration enhancers and the reasons why penetration enhancers with HLB values ​​of 3 to 5 are preferred. The IVPT results for Examples 3 to 7 are shown in Figure 2, and the equations for the permeation amount (Q) versus time (t) are shown in Table 1.

[0059] In Examples 8-9, different penetration enhancers and plasticizers with HLB (HLB: Hydrophile Lipophilic Balance) values ​​of 3-5 were further combined and optimized and screened by IVRT (IVRT: In Vitro Release Testing) and IVPT (IVPT: In Vitro Permeation Testing). The IVPT results for Examples 8-9 are shown in Figure 3, and the permeation rate (Q)-time (t) equation is shown in Table 2.

[0060] In this invention, the in vitro release test (IVRT) study was conducted using the Chinese Pharmacopoeia (Chinese Pharmacopoeia) (2020 edition) 0931, Method 4 (stirred paddle dish method). The cumulative release amount within a certain sampling time was calculated using a release meter and high performance liquid chromatography, and a plot of the rasagiline release rate (%) versus time (t) was drawn. The implementation plan for IVRT is as follows:

[0061] Release medium: pH 4.5 acetate buffer (weigh out 2.99 g of sodium acetate trihydrate, add 1000 mL of water, dissolve, and adjust the pH to 4.5 with acetic acid), pH 7.4 phosphate buffer (weigh out 6.80 g of potassium dihydrogen phosphate, weigh out 1.564 g of sodium hydroxide, add 1000 mL of water, and dissolve).

[0062] Medium volume / temperature / rotation speed / sample volume: 900mL, 32±0.5℃, 50r / min, 3 samples / time.

[0063] Sampling times: 0.5, 1, 2, 4, 8, 12, 24, 26, 48, 60, 72 h (generally 24 h).

[0064] Chromatography conditions: Chromatography column: Agilent Zorbax SB-C18 4.6 × 250 mm, 5 μm, mobile phase: 10 mM KH2PO4:ACN = 80:20, flow rate: 1.0 mL / min, column temperature: 40 °C, detection wavelength: 210 nm, injection volume: 50 μl, sampling time: 6 min.

[0065] In vitro permeation testing (IVPT) was performed using Franz diffusion cells (in vitro transdermal experimental system) and Bama pig skin to evaluate the permeability of rasagiline mesylate. The receptor solution was 0.01% gentamicin sulfate (PBS, pH 7.4). The content of rasagiline in the receptor cells at different sampling points was measured by high-performance liquid chromatography, and the cumulative permeation amount of rasagiline was calculated and plotted as a cumulative permeation amount (Q) versus time (t).

[0066] In addition, to further demonstrate that the patch has relatively good usability, the adhesive strength and peel strength of the transdermal patch prepared by the formulation and process of [Example 9] were further tested.

[0067] Finally, to further demonstrate the good stability of the patch, a stability test was carried out on the transdermal patch prepared with the formulation and process of Example 9. The results are shown in Table 3.

[0068] Example 1 JPEG2026504532000002.jpg65148

[0069] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, triethyl citrate, propylene glycol monocaprylate, polyglycerol oleate, and absolute ethanol until all solids are completely dissolved, resulting in a clear, homogeneous solution; (2) Add DURO-TAK387-2052 to the above liquid, and mix and stir until homogeneous, resulting in an intermediate solution.

[0070] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 1022 release film (protective layer) is coated to a wet film thickness of 300 μm, and then dried using a three-stage drying method: drying at 20°C for 5 minutes, drying at 50°C for 5 minutes, and drying at 70°C for 10 minutes. The resulting dried substrate has a thickness of 120 μm.

[0071] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 9738 backing film (backing layer) is laminated to the dry substrate to form a composite.

[0072] The patch prepared by the above formula and process precipitated a large amount of crystals after being left at room temperature for 3 days.

[0073] Example 2 JPEG2026504532000003.jpg73148

[0074] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, triethyl citrate, propylene glycol monocaprylate, polyglycerol oleate, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0075] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 1022 release film (protective layer) is coated to a wet film thickness of 300 μm, and then dried using a three-stage drying method: drying at 25°C for 5 minutes, drying at 55°C for 8 minutes, and drying at 75°C for 10 minutes. The resulting dried substrate has a thickness of 120 μm.

[0076] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 9738 backing film (backing layer) is laminated with the above dry substrate to form a composite, and then a 10 cm 2 Cut into patches.

[0077] The patches prepared by the above formulation and process showed no crystal precipitation after 60 days under four conditions: room temperature, high temperature (40°C), refrigeration (4°C), and freezing (-18°C), demonstrating that PVPP can carry the water-soluble drug rasagiline mesylate.

[0078] Examples 3-7 examine IVPT by preparing formulations containing no penetration enhancer and those containing penetration enhancers with HLB values ​​of 1 to 5, further illustrating the need for penetration enhancers and the reasons for selecting penetration enhancers with HLB values ​​of 3 to 5. The permeation quantity (Q) versus time (t) equations for Examples 3-7 are shown in Table 1, and the IVPT plots are shown in Figure 2.

[0079] Example 3: No penetration enhancer JPEG2026504532000004.jpg73148

[0080] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0081] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 1022 release film (protective layer) is coated to a wet thickness of 300 μm, and then dried using a three-stage drying method: drying at 20°C for 10 minutes, drying at 60°C for 10 minutes, and drying at 75°C for 10 minutes. The resulting dried substrate has a thickness of 120 μm.

[0082] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 9730 backing film (backing layer) was laminated to the above dry substrate to form a composite, and then a 10 cm 2 The IVPT results are shown in Figure 2.

[0083] Example 4 Penetration enhancer: glycerin monolinoleate JPEG2026504532000005.jpg81148

[0084] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, glycerin monolinoleate, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0085] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 1022 release film (protective layer) is coated to a wet film thickness of 300 μm, and then dried using a three-stage drying method: drying at 25°C for 10 minutes, drying at 50°C for 8 minutes, and drying at 80°C for 5 minutes. The resulting dried substrate has a thickness of 120 μm.

[0086] Tape 3: Laminate, combine and cut. SCOTCHPAK TM 1109 The backing film (backing layer) is laminated with the above dry substrate to form a composite, and then a 10 cm 2 The IVPT results are shown in Figure 2.

[0087] Example 5 Penetration enhancer: Glycerin monooleate JPEG2026504532000006.jpg81148

[0088] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, glycerin monooleate, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-4098 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0089] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 2054 release film (protective layer) is coated to a wet film thickness of 300 μm, and then dried using a three-stage drying method: drying at 25°C for 8 minutes, drying at 55°C for 10 minutes, and drying at 80°C for 5 minutes. The resulting dried substrate has a thickness of 120 μm.

[0090] Tape 3: Laminate, combine and cut. SCOTCHPAK TMThe 9730 backing film (backing layer) is laminated with the above dry substrate to form a composite, and then a 10cm 2 The IVPT results are shown in Figure 2.

[0091] Example 6 Penetration enhancer: Polyglycerol oleate JPEG2026504532000007.jpg81148

[0092] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, polyglycerol oleate, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0093] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 1022 release film (protective layer) is coated to a wet thickness of 300 μm, and then dried using a three-stage drying method: drying at 20°C for 10 minutes, drying at 65°C for 8 minutes, and drying at 75°C for 10 minutes. The resulting dried substrate has a thickness of 120 μm.

[0094] Tape 3: Laminate, combine and cut. SCOTCHPAK TM 9738 backing film (backing layer) is laminated with the above dry substrate to form a composite, and then a further 10 cm 2 The IVPT results are shown in Figure 2.

[0095] Example 7 Penetration Enhancer: Propylene Glycol Monocaprylate JPEG2026504532000008.jpg82150

[0096] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, propylene glycol monocaprylate, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2287 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0097] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 2504 release film (protective layer) is coated to a wet thickness of 300 μm, and then dried using a three-stage drying method: drying at 25°C for 10 minutes, drying at 60°C for 10 minutes, and drying at 75°C for 10 minutes. The resulting dried substrate has a thickness of 120 μm.

[0098] Tape 3: Laminate, combine and cut. SCOTCHPAK TM 1109 The backing film (backing layer) is laminated with the above dry substrate to form a composite, and then a 10 cm 2 The IVPT results are shown in Figure 2.

[0099] Table 1. Qt equations for formulations in Examples 3 to 7 JPEG2026504532000009.jpg87170

[0100] Here, J represents the penetration rate. (Note: R 2 is a parameter used to evaluate the fitting effect of a linear regression model. When the value is 1, it indicates that all data points of the model are perfectly on the regression line. The closer the value is to 1, the better the fitting effect and the higher the model's fitness. The closer the value is to 0, the worse the fitting effect and the lower the model's fitness.

[0101] Analysis of results of Examples 3 to 7: Permeation rate: No penetration enhancer (J = 0.1475) < Glycerin monooleate Peceol (HLB = 1) (J = 0.8527) < Glycerin monolinoleate MCC (HLB = 1) (J = 0.9944) < Propylene glycol monocaprylate C90 (HLB = 5) (J = 1.5849) < Polyglycerol oleate CC497 (HLB = 3) (J = 1.9380). All formulations containing penetration enhancers had improved J values ​​to different degrees compared with formulations without penetration enhancers. The formulations containing propylene glycol monocaprylate and polyglycerol fatty acid ester, respectively, had permeation rates 10-fold and 13-fold higher than formulations without penetration enhancers. Therefore, penetration enhancers with an HLB of 3-5 have better permeation enhancing effects in this formulation, and for rasagiline mesylate patches, penetration enhancers with an HLB of 3-5 are preferred.

[0102] Examples 8-9 further combine different penetration enhancers with HLB between 3 and 5 with the plasticizer triethyl citrate to control the delivery rate.

[0103] The IVRT in vitro release of Examples 8-9 is shown in Table 2. The IVRT is shown in Figure 3. The permeation rate (Q)-time (t) equation is shown in Table 3.

[0104] Example 8 Penetration Enhancer Combinations JPEG2026504532000010.jpg89148

[0105] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, propylene glycol monocaprylate, polyglycerol oleate, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0106] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 1022 release film (protective layer) is coated to a wet film thickness of 300 μm, and then dried using a three-stage drying method: drying at 25°C for 10 minutes, drying at 65°C for 8 minutes, and drying at 80°C for 5 minutes. The resulting dried substrate has a thickness of 120 μm.

[0107] Tape 3: Laminate, combine and cut. SCOTCHPAK TM 9738 backing film (backing layer) is laminated with the above dry substrate to form a composite, and then a further 10 cm 2 Cut into patches

[0108] Example 9 Penetration Enhancer Combinations JPEG2026504532000011.jpg89148

[0109] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, propylene glycol monocaprylate, polyglycerol oleate, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0110] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 1022 release film (protective layer) is coated to a wet thickness of 300 μm, and then dried using a three-stage drying method: drying at 20°C for 10 minutes, drying at 60°C for 10 minutes, and drying at 75°C for 10 minutes. The resulting dried substrate has a thickness of 120 μm.

[0111] Tape 3: Laminate, combine and cut. SCOTCHPAKTM 9738 backing film (backing layer) is laminated with the above dry substrate to form a composite, and then a further 10 cm 2 Cut into patches.

[0112] Table 2. IVRT results for Examples 8 and 9 JPEG2026504532000012.jpg74148

[0113] Table 3: Relationship between cumulative permeation amount (Q) and time (t) in Examples 8 and 9 JPEG2026504532000013.jpg50149

[0114] Analysis of results of Examples 8-9: A comparison of the IVRT between [Example 8] and [Example 9] revealed that the IVRT release behavior of the formulations was nearly identical, with [Example 9] showing a slightly higher release rate than [Example 8]. It can be inferred that a penetration enhancer with a lower HLB value may be more beneficial for drug release. Comparing [Example 8] and [Example 9], it can be seen that under the same total amount of penetration enhancer (6%), the permeation rate of 5% plasticizer was faster than that of 4% plasticizer. Considering the conclusion that [Example 9] showed a slightly higher release rate than [Example 8], increasing the plasticizer ratio increases drug release, which in turn increases the skin drug concentration gradient over the same time period. Based on Fick's law, this is more beneficial for permeation progression. Therefore, it can be inferred that a formulation with a higher release rate may also have a correspondingly faster permeation rate.

[0115] In addition, to further demonstrate that the patch has relatively good usage performance, the transdermal patch prepared with the formulation and process of [Example 9] was further tested on the following parameters:

[0116] Peel strength: The test was performed using the 180° peel test method described in the "Chinese Pharmacopoeia" 2020 edition, Part 4, General Provisions 0952, Method 3, "Determination of Peel Strength." The test was repeated 6 times, and the average value was calculated as 1.15N / 50mm.

[0117] Finally, to further demonstrate that the patch has good stability, a stability test was further carried out on the transdermal patch prepared with the formulation and process of Example 9. The results are shown in Table 4.

[0118] Table 4. Changes in active ingredient content of transdermal patches under different conditions JPEG2026504532000014.jpg17149

[0119] The above embodiment is a specific embodiment corresponding to Scheme 1 and Method 1, and the following embodiment is a specific embodiment corresponding to Scheme 2 and Method 2.

[0120] In the following description, Examples 1' to 6' compare formulations containing cross-linked polyvidone with those not containing cross-linked polyvidone, with the purpose of demonstrating that cross-linked polyvidone can carry the water-soluble drug rasagiline mesylate, and that the final drug loading of the system is 0.5 to 5.0% rasagiline mesylate (a higher loading would make the process difficult to implement and prevent industrial production and preparation), and that a mass ratio of rasagiline mesylate to cross-linked polyvidone of 1:5 to 1:15 is relatively appropriate.

[0121] Examples 7' to 11' compare and discuss IVPT (IVPT: In Vitro Permeation Testing) of formulations containing no penetration enhancer and formulations containing penetration enhancers with different HLB values ​​(HLB: Hydrophilic Lipophilic Balance), further explaining the necessity of using a penetration enhancer and the reasons why polyglycerol fatty acid esters are preferred. The permeation amount (Q)-time (t) equations for Examples 7' to 11' are shown in Table 5.

[0122] Examples 12' to 14' compare and discuss the IVRT (IVRT: In Vitro Release Testing) of formulations containing acetylpropionic acid, octanoic acid, and undecenoic acid to further explain why acetylpropionic acid is preferred as a release promoter. The IVRT results of Examples 12' to 14' are shown in Table 6.

[0123] Examples 15'-17' further demonstrate that IVRT and IVPT can be considered to achieve controllable drug delivery rates by combining different ratios of permeation enhancers and release enhancers. The results of IVRT and IVPT are shown in Tables 7 and 8.

[0124] In this invention, the in vitro release test (IVRT) study is conducted using the fourth method (stirred paddle dish method) of the Chinese Pharmacopoeia (2020 edition) 0931. The cumulative release amount within a certain sampling time is calculated using a release meter and high performance liquid chromatography, and a plot of the release rate (%) of rasagiline versus time (t) is drawn. The implementation scheme of IVRT is as follows:

[0125] Release medium: pH 4.5 acetate buffer.

[0126] Medium volume / temperature / rotation speed / sample volume: 900mL, 32±0.5℃, 50r / min, 3 samples / time. Sampling time points: 0.5h, 1h, 2h, 4h, 8h, 12h, 18h, 24h.

[0127] Chromatography conditions: Chromatography column: Agilent Zorbax SB-C18 4.6 × 250 mm, 5 μm, mobile phase: 10 mM KH2PO4:ACN = 80:20, flow rate: 1.0 mL / min, column temperature: 40 °C, detection wavelength: 210 nm, injection volume: 50 μl, sampling time: 6 min.

[0128] In vitro permeation testing (IVPT) was performed using Franz diffusion cells (in vitro transdermal experimental system) and Bama pig skin to evaluate the permeability of rasagiline mesylate. The receptor solution was 0.01% gentamicin sulfate (PBS, pH 7.4). The content of rasagiline in the receptor cell at different sampling points was measured by high-performance liquid chromatography, and the cumulative permeation amount of rasagiline was calculated and plotted as a function of cumulative permeation amount (Q) versus time (t).

[0129] In addition, to further demonstrate that the patch has relatively good usability, the transdermal patch prepared with the formulation and process of Example 15' was further tested for adhesive strength and peel strength, and the results are shown in Table 9.

[0130] Finally, to further demonstrate that the patch has good stability, the transdermal patch prepared with the formulation and process of Example 15' was further subjected to stability testing, and the results are shown in Table 10.

[0131] Examples 1' to 6' The main inventive point of the present invention is to obtain a patch with a high drug loading by adding PVPP to load the water-soluble drug rasagiline mesylate. Therefore, an experiment was designed to explore the final formulation by considering three variables: whether to add PVPP, the amount of PVPP added, and the ratio of PVPP to rasagiline mesylate.

[0132] The experimental design is shown in the table below. JPEG2026504532000015.jpg165170

[0133] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, triethyl citrate, polyglycerol oleate, and absolute ethanol until all solids are completely dissolved, resulting in a clear, homogeneous solution; (2) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogeneous, resulting in an intermediate solution.

[0134] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 2504 protective layer is applied to a wet film thickness of 300 μm, and then dried in a three-stage drying process: 8 minutes at 30°C, 8 minutes at 65°C, and 10 minutes at 80°C. The resulting dried substrate has a thickness of 120 μm.

[0135] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 1109 backing layer is laminated with the dry substrate to form a composite, and then a further 10 cm 2 Cut into patches.

[0136] The patches prepared by the above formulation and process were left at room temperature for 3 days, and then observed under a polarizing microscope for the presence or absence of crystallization.

[0137] Comparing Example 1' and Example 3', it was found that crystallization occurred regardless of whether the drug loading was high (2%) or low (0.1%), or whether PVPP was not included. Quantitative analysis and statistics were performed on the amount of crystallization (see Figure 4). The crystallization area was calculated as a percentage of the total area. Examples 4' to 6' show a comparison of the micromorphology observed under unpolarized light and polarized light, where no crystallization was observed.

[0138] Examples 4' to 6' demonstrate that adding PVPP can prevent crystallization. At the same time, the optimum ratio of PVPP to drug was explored, and the maximum drug loading of the system was less than 5.0.

[0139] The following examples further address the permeation, release and stable storage issues.

[0140] Examples 7' to 11' further compare and discuss IVPT of formulations without penetration enhancers and formulations containing penetration enhancers with different HLB values, further explaining the necessity of using penetration enhancers and the reasons why polyglycerol fatty acid esters are preferred. The permeation amount (Q)-time (t) equations for Examples 7' to 11' are shown in Table 5.

[0141] Example 7' No penetration enhancer JPEG2026504532000016.jpg73149

[0142] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, acetylpropionic acid, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0143] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 1022 protective layer is applied to a wet film thickness of 300 μm, and then dried in a three-stage drying process: 10 minutes at 25°C, 10 minutes at 60°C, and 10 minutes at 75°C. The resulting dried substrate has a thickness of 120 μm.

[0144] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 9738 backing layer is laminated to the dry substrate to form a composite, and then a further 10 cm 2 Cut into patches.

[0145] Example 8' Penetration enhancer: Glycerin monolinoleate JPEG2026504532000017.jpg83149

[0146] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, glycerin monolinoleate, acetylpropionic acid, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0147] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 1022 protective layer is applied to a wet film thickness of 300 μm, and then dried in a three-stage drying process: 10 minutes at 25°C, 10 minutes at 60°C, and 10 minutes at 75°C. The resulting dried substrate has a thickness of 120 μm.

[0148] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 9738 backing film is laminated to the dry substrate to form a composite, and then a further 10 cm 2 Cut into patches.

[0149] Example 9' Penetration enhancer: glycerin monooleate JPEG2026504532000018.jpg81148

[0150] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, glycerin monooleate, acetylpropionic acid, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0151] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 1022 protective layer is applied to a wet film thickness of 300 μm, and then dried in a three-stage drying process: 10 minutes at 25°C, 10 minutes at 60°C, and 10 minutes at 75°C. The resulting dried substrate has a thickness of 120 μm.

[0152] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 9738 backing layer is laminated to the dry substrate to form a composite, and then a further 10 cm 2 Cut into patches.

[0153] Example 10' Penetration Enhancer: Polyglycerol Oleate JPEG2026504532000019.jpg81149

[0154] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, polyglycerol oleate, acetylpropionic acid, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0155] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 1022 protective layer is applied to a wet film thickness of 300 μm, and then dried in a three-stage drying process: 10 minutes at 25°C, 10 minutes at 60°C, and 10 minutes at 75°C. The resulting dried substrate has a thickness of 120 μm.

[0156] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 9738 backing layer is laminated to the dry substrate to form a composite, and then a further 10 cm 2 Cut into patches.

[0157] Example 11' Penetration enhancer: Propylene glycol monocaprylate JPEG2026504532000020.jpg81148

[0158] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, propylene glycol monocaprylate, acetylpropionic acid, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0159] Tape 2: Apply the intermediate solution to the SCOTCHPAK film and remove the solvent by drying. TM The 1022 protective layer is applied to a wet film thickness of 300 μm, and then dried in a three-stage drying process: 10 minutes at 25°C, 10 minutes at 60°C, and 10 minutes at 75°C. The resulting dried substrate has a thickness of 120 μm.

[0160] Tape 3: Laminate, combine and cut. SCOTCHPAK TMThe 9738 backing layer is laminated to the dry substrate to form a composite, and then a further 10 cm 2 Cut into patches.

[0161] Table 5. Qt equations for formulations of Examples 7' to 11' JPEG2026504532000021.jpg87170

[0162] Here, J represents the penetration rate. (Note: R 2 is a parameter used to evaluate the fitting effect of a linear regression model. When the value is 1, it indicates that all data points of the model are perfectly on the regression line. The closer the value is to 1, the better the fitting effect and the higher the model's fitness. The closer the value is to 0, the worse the fitting effect and the lower the model's fitness.

[0163] Analysis of the results of Examples 7' to 11': All formulations containing penetration enhancers showed improvements in J values ​​to varying degrees compared to formulations without penetration enhancers, with polyglycerol fatty acid esters showing the best penetration enhancing effect, making polyglycerol fatty acid esters the preferred penetration enhancer for rasagiline mesylate patches.

[0164] Examples 12' to 14' compare and discuss the IVRT of formulations containing acetylpropionic acid, octanoic acid, and undecenoic acid to further explain why acetylpropionic acid is preferred as a release-enhancing agent. The IVRT results are shown in Table 6.

[0165] Example 12' Release promoter: acetylpropionic acid JPEG2026504532000022.jpg82148

[0166] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, polyglycerol fatty acid ester, acetylpropionic acid, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the liquid, and mix and stir until uniform, resulting in an intermediate solution.

[0167] Tape 2: Coating and drying to remove the solvent. The intermediate solution is coated onto the 75E-0010BD protective layer to a wet thickness of 300 μm, followed by drying. A three-stage drying method is used: drying at 25°C for 10 minutes, drying at 65°C for 8 minutes, and drying at 80°C for 8 minutes. The resulting dried substrate has a thickness of 120 μm.

[0168] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 9738 backing layer is laminated to the dry substrate to form a composite, and then a further 10 cm 2 The results of IVRT are shown in Table 6.

[0169] Example 13' Release promoter: Octanoic acid JPEG2026504532000023.jpg81149

[0170] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, polyglycerol fatty acid ester, octanoic acid, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0171] Tape 2: Coating and drying to remove the solvent. The intermediate solution is coated onto the 75E-0010BD protective layer to a wet thickness of 300 μm, followed by drying. A three-stage drying method is used: drying at 25°C for 10 minutes, drying at 65°C for 8 minutes, and drying at 80°C for 8 minutes. The resulting dried substrate has a thickness of 120 μm.

[0172] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 9738 backing layer is laminated to the dry substrate to form a composite, and then a further 10 cm 2 The results of IVRT are shown in Table 6.

[0173] Example 14' Release promoter: Undecenoic acid JPEG2026504532000024.jpg81149

[0174] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, polyglycerol fatty acid ester, undecenoic acid, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0175] Tape 2: Coating and drying to remove the solvent. The intermediate solution is coated onto the 75E-0010BD protective layer to a wet thickness of 300 μm, followed by drying. A three-stage drying method is used: drying at 25°C for 10 minutes, drying at 65°C for 8 minutes, and drying at 80°C for 8 minutes. The resulting dried substrate has a thickness of 120 μm.

[0176] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 9738 backing layer is laminated to the dry substrate to form a composite, and then a further 10 cm 2The results of IVRT are shown in Table 6.

[0177] Table 6. IVRT for Examples 12'-14' JPEG2026504532000025.jpg72170

[0178] Analysis of the results of Examples 12' to 14': The release rate before 2 hours was Example 12' (acetylpropionic acid) > Example 13' (octanoic acid) > Example 14' (undecenoic acid), and after 2 hours, the three gradually became equivalent. Therefore, acetylpropionic acid has a relatively strong release-promoting effect in the early stage of release.

[0179] Examples 15'-17' further demonstrate that IVPT can be studied by combining different ratios of permeation enhancers and release enhancers to achieve controllable drug delivery rates. The results of IVRT and IVPT are shown in Tables 7 and 8.

[0180] Example 15' JPEG2026504532000026.jpg81149

[0181] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, polyglycerol fatty acid ester, acetylpropionic acid, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the liquid, and mix and stir until uniform, resulting in an intermediate solution.

[0182] Tape 2: Coating and drying to remove the solvent. The intermediate solution is coated onto the 75E-0010BD protective layer to a wet thickness of 300 μm, followed by drying. A three-stage drying method is used: drying at 25°C for 10 minutes, drying at 60°C for 10 minutes, and drying at 80°C for 8 minutes. The resulting dry substrate has a thickness of 120 μm.

[0183] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 1109 backing layer is laminated with the dry substrate to form a composite, and then a further 10 cm 2 The results of IVRT and IVPT are shown in Tables 7 and 8.

[0184] Example 16' JPEG2026504532000027.jpg81149

[0185] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, polyglycerol fatty acid ester, acetylpropionic acid, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the liquid, and mix and stir until uniform, resulting in an intermediate solution.

[0186] Tape 2: Coating and drying to remove the solvent. The intermediate solution is coated onto the 75E-0010BD protective layer to a wet thickness of 300 μm, followed by drying. A three-stage drying method is used: drying at 25°C for 10 minutes, drying at 60°C for 10 minutes, and drying at 80°C for 8 minutes. The resulting dry substrate has a thickness of 120 μm.

[0187] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 1109 backing layer is laminated with the dry substrate to form a composite, and then a further 10 cm 2 The results of IVRT and IVPT are shown in Tables 7 and 8.

[0188] Example 17' JPEG2026504532000028.jpg81149

[0189] Tape 1: Prepare the drug-containing adhesive layer (substrate layer): (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, polyglycerol fatty acid ester, acetylpropionic acid, and absolute ethanol until all solids are completely dissolved, resulting in a clear, uniform solution; (2) Add cross-linked polyvidone to the solution, premix and stir evenly, and then homogenize to obtain a white, milky liquid; (3) Add DURO-TAK387-2052 to the solution, and mix and stir until uniform, resulting in an intermediate solution.

[0190] Tape 2: Coating and drying to remove the solvent. The intermediate solution is coated onto the 75E-0010BD protective layer to a wet thickness of 300 μm, followed by drying. A three-stage drying method is used: drying at 25°C for 10 minutes, drying at 60°C for 10 minutes, and drying at 80°C for 8 minutes. The resulting dry substrate has a thickness of 120 μm.

[0191] Tape 3: Laminate, combine and cut. SCOTCHPAK TM The 1109 backing layer is laminated with the dry substrate to form a composite, and then a further 10 cm 2 The results of IVRT and IVPT are shown in Tables 7 and 8.

[0192] Table 7 IVRT for Examples 15' to 17' JPEG2026504532000029.jpg71170

[0193] Table 8: Relationship between cumulative permeation amount (Q) and time (t) for Examples 15' to 17' JPEG2026504532000030.jpg65149

[0194] Analysis of the results of Examples 15' to 17': In Examples 15' to 17', the release rate increased with increasing acetylpropionic acid, and the permeation rate gradually decreased with decreasing polyglycerol fatty acid ester. The release-enhancing effect of acetylpropionic acid and the permeation-enhancing effect of polyglycerol fatty acid ester are further explained. The release rate and permeation rate of the drug can be controlled by adjusting the amount of release enhancer and permeation enhancer.

[0195] In addition, to further demonstrate that the patch has relatively good usage performance, the transdermal patch prepared by the formulation and process of Example 15' was further tested for peel strength and adhesive durability.

[0196] Finally, to further demonstrate that the patch has good stability, a stability test was further carried out on the transdermal patch prepared with the formulation and process of Example 15'. The results are shown in Table 9.

[0197] Table 9. Peel strength and adhesion durability test results for Example 15' JPEG2026504532000031.jpg18150

[0198] Finally, to further demonstrate that the patch has good stability, the transdermal patch prepared with the formulation and process of Example 15' was further subjected to stability testing, and the results are shown in Table 10.

[0199] Table 10: Changes in active ingredient content of transdermal patches under different conditions JPEG2026504532000032.jpg32170

[0200] Those skilled in the art should understand that in the process of preparing the transdermal patch of the present application, the product obtained in the process of preparing the tape 1, i.e., the drug-containing adhesive layer (substrate layer, substrate mixture), is an intermediate product (drug-containing adhesive layer (substrate layer, substrate mixture)), and in order to facilitate mixing and subsequent transfers in the preparation process, an organic solvent (an organic solvent that evaporates easily and is easily removed, such as ethanol or isopropanol) may be added during the process to aid dissolution, dilute, and reduce the viscosity of the mixture. Alternatively, an organic solvent (e.g., in the case of an adhesive that is liquid at room temperature and pressure, such as an acrylate pressure-sensitive adhesive) may not be added. Therefore, the prepared intermediate product (drug-containing adhesive layer (substrate layer, substrate mixture)) may or may not contain the organic solvent. In the preparation process of the present application, the organic solvent ethanol was added based on the fact that adding an organic solvent to aid dissolution, dilute, and reduce the viscosity of the mixture can facilitate mixing and subsequent transfers in the preparation process.

[0201] It should be understood by those skilled in the art that through the process of removing the solvent by drying in the tape 2, the final prepared transdermal patch should be free of organic solvents or contain a very small amount of organic solvents that meets the requirements of the pharmacopeia or pharmaceutical quality.

[0202] It should be understood by those skilled in the art that the embodiments of the present invention shown in the above description are merely illustrative and are not intended to limit the present invention. The objects of the present invention have been fully and effectively achieved. The principles of the function and structure of the present invention have been shown and explained in the above examples, and the embodiments of the present invention may be modified or altered in any way without departing from the above principles.

Claims

1. 1. A rasagiline mesylate-containing transdermal patch comprising a backing layer, a matrix layer and a protective layer, wherein the matrix layer contains the following components in weight percent contents: 0.5-5.0% rasagiline mesylate, 40-80% adhesive, 3-25% cross-linked polyvidone, 1-5% crystallization inhibitor, 1-15% permeation enhancer, 1-10% plasticizer and 0.001-0.5% antioxidant, the weight ratio of rasagiline mesylate to cross-linked polyvidone being 1:5-1:15, and the amount of adhesive is adjusted to adjust the final weight percent to 100%, and the matrix layer further contains a release enhancer in weight percent content of 0.1-5.0%, the release enhancer being one or a combination of several selected from the group consisting of acetylpropionic acid, octanoic acid and undecenoic acid.

2. 1. A rasagiline mesylate-containing transdermal patch comprising a backing layer, a matrix layer and a protective layer, wherein the matrix layer contains the following components in weight percent contents: 0.5-5.0% rasagiline mesylate, 40-80% adhesive, 3-25% cross-linked polyvidone, 0.1-5.0% release enhancer, 1-15% penetration enhancer, 0.5-10% plasticizer and 0.001-0.5% antioxidant, wherein the weight ratio of rasagiline mesylate to cross-linked polyvidone is 1:5-1:15, the amount of adhesive is adjusted to a final weight percent of 100%, and the release enhancer is one or a combination of several selected from the group consisting of acetylpropionic acid, octanoic acid and undecenoic acid.

3. The rasagiline mesylate-containing transdermal patch according to claim 1 or 2, wherein the release promoter is acetylpropionic acid.

4. 2. The rasagiline mesylate-containing transdermal patch according to claim 1, wherein the mass ratio of rasagiline mesylate to the crystallization inhibitor is 3:1 to 3:

5.

5. 2. The rasagiline mesylate-containing transdermal patch according to claim 1, wherein the mass ratio of the plasticizer to the penetration enhancer is 1:1 to 1:

5.

6. 3. The rasagiline mesylate-containing transdermal patch according to claim 2, wherein the mass ratio of the release enhancer to rasagiline mesylate is 1:1 to 1:

4.

7. 3. The rasagiline mesylate-containing transdermal patch according to claim 2, wherein the mass ratio of the plasticizer to the penetration enhancer is 1:1 to 1:

10.

8. 3. The rasagiline mesylate-containing transdermal patch according to claim 2, wherein the mass ratio of the release enhancer to the penetration enhancer is 1:1 to 1:

15.

9. 3. The rasagiline mesylate-containing transdermal patch according to claim 1, wherein the adhesive is selected from acrylate pressure-sensitive adhesives.

10. The rasagiline mesylate-containing transdermal patch according to claim 9, wherein the acrylate pressure-sensitive adhesive is one or a combination of several selected from the group consisting of DURO-TAK 387-2516, DURO-TAK 387-2052, DORO-TAK 87-4098 and DORO-TAK 387-2287.

11. The rasagiline mesylate-containing transdermal patch according to claim 1, wherein the crystallization inhibitor is at least one substance selected from the group consisting of polyvidone K90, polyvidone K30, polyvidone K25, polyvidone K17, polyvidone K12, and copovidone VA64.

12. The rasagiline mesylate-containing transdermal patch according to claim 1, wherein the crystallization inhibitor is one or a combination of several selected from the group consisting of polyvidone K25, polyvidone K17, polyvidone K12 and copovidone VA64.

13. A rasagiline mesylate-containing transdermal patch according to claim 1 or 2, characterized in that the penetration enhancer is at least one substance selected from propylene glycol monocaprylate, polyglycerol fatty acid ester, glycerin monooleate, glycerin monolinoleate, glycerin monostearate, Span 80 and Span 60.

14. 14. The rasagiline mesylate-containing transdermal patch according to claim 13, wherein the penetration enhancer is selected from propylene glycol monocaprylate or polyglycerol fatty acid esters.

15. 3. The rasagiline mesylate-containing transdermal patch according to claim 1, wherein the plasticizer is one or a combination of several selected from the group consisting of triethyl citrate, glycerin triacetate, and dibutyl phthalate.

16. 16. The rasagiline mesylate-containing transdermal patch according to claim 15, wherein the plasticizer is selected from triethyl citrate.

17. A transdermal patch containing rasagiline mesylate according to claim 1 or 2, characterized in that the antioxidant is one or a combination of several selected from vitamin E (tocopherol), tocopherol acetate, tocopherol succinate, tocopherol nicotinate, tocopherol palmitate, tocopherol linoleate and tocopherol phosphate.

18. The rasagiline mesylate-containing transdermal patch according to claim 17, characterized in that the antioxidant is selected from vitamin E (tocopherol).

19. The backing layer is SCOTCHPAK ＴＭ 9738, SCOTCHPAK ＴＭ 9730, SCOTCHPAK ＴＭ 1109, and the protective layer is SCOTCHPAK ＴＭ 1022, SCOTCHPAK ＴＭ 3. The rasagiline mesylate-containing transdermal patch according to claim 1, wherein the rasagiline mesylate-containing transdermal patch is one selected from the group consisting of 2504 and 75E-0010BD.

20. a drug-containing matrix layer tape 1 prepared by weighing out 0.5-5.0% rasagiline mesylate, 1-5% crystallization inhibitor, 1-15% permeation enhancer, 0.1-5.0% release enhancer, 1-10% plasticizer, and 0.001-0.5% antioxidant in a solvent and mixing and stirring until all solids are completely dissolved to obtain a uniform solution; adding 3-25% cross-linked polyvidone to the uniform solution and premixing until fully swollen, followed by homogenization to obtain a white milky liquid; and adding 40-80% adhesive to the white milky liquid and mixing and stirring until uniform to obtain an intermediate solution; a tape 2 for removing the solvent by coating and drying the intermediate solution onto the protective layer, so that the wet film has a thickness of 100-500 μm, and then drying the intermediate solution to obtain a dry substrate, so that the dry film has a thickness of 20-250 μm; A laminate / composite / cutting tape 3 is used to laminate the backing layer onto the dry substrate and cut it into patches. Including, A method for preparing a transdermal patch containing rasagiline mesylate, characterized in that the release-enhancing agent is one or a combination of several selected from acetylpropionic acid, octanoic acid, and undecenoic acid, the mass ratio of rasagiline mesylate to cross-linked polyvidone is 1:5 to 1:15, and the amount of adhesive is adjusted so that the final mass percentage is 100%.

21. a drug-containing matrix layer tape 1 prepared by weighing out 0.5-5.0% rasagiline mesylate, 0.1-5.0% release enhancer, 1-15% penetration enhancer, 0.5-10% plasticizer, and 0.001-0.5% antioxidant in a solvent and mixing and stirring until all solids are completely dissolved to obtain a uniform solution; adding 3-25% cross-linked polyvidone to the uniform solution and premixing until fully swollen, followed by homogenization to obtain a white milky liquid; and adding 40-80% adhesive to the white milky liquid and mixing and stirring until uniform to obtain an intermediate solution; a tape 2 for removing the solvent by coating and drying the intermediate solution onto a protective layer, the wet film thickness being 100-500 μm, and then drying to obtain a dry substrate, the dry film thickness being 20-250 μm; The backing layer is laminated with the dry substrate to form a composite, and then cut into patches using a laminate composite and cutting tape 3. Including, A method for preparing a transdermal patch containing rasagiline mesylate, characterized in that the release-enhancing agent is one or a combination of several selected from acetylpropionic acid, octanoic acid, and undecenoic acid, the mass ratio of rasagiline mesylate to cross-linked polyvidone is 1:5 to 1:15, and the amount of adhesive is adjusted so that the final mass percentage is 100%.

22. 22. The method according to claim 20 or 21, wherein the solvent in tape 1 is one or a combination of absolute ethanol or isopropanol.

23. 23. The method of claim 22, wherein the solvent in tape 1 is selected from absolute ethanol.

24. The method according to claim 21 or 22, wherein the drying in step 2 is performed in a three-stage drying mode, in which the first stage is drying at 20-30°C for 2-10 minutes, the second stage is drying at 45-65°C for 2-10 minutes, and the third stage is drying at 65-85°C for 2-10 minutes.

25. The method according to claim 24, characterized in that in the first stage of drying in step 2, the drying is carried out at 20-25°C for 2-10 minutes.

26. 1. A matrix mixture for preparing a rasagiline mesylate transdermal patch, comprising the following components in weight percent contents: 0.5-5.0% rasagiline mesylate, 40-80% adhesive, 3-25% cross-linked polyvidone, 1-5% crystallization inhibitor, 1-15% permeation enhancer, 0.1-5.0% release enhancer, 1-10% plasticizer, and 0.001-0.5% antioxidant, wherein the weight ratio of rasagiline mesylate to cross-linked polyvidone is 1:5-1:15, and the amount of adhesive is adjusted to adjust the final weight percent to 100%, and the release enhancer is one or a combination of several selected from the group consisting of acetylpropionic acid, octanoic acid, and undecenoic acid.

27. 1. A substrate mixture for preparing a rasagiline mesylate transdermal patch, comprising components in the following weight percent contents: 0.5-5.0% rasagiline mesylate, 40-80% adhesive, 3-25% cross-linked polyvidone, 0.1-5.0% release enhancer, 1-15% penetration enhancer, 0.5-10% plasticizer, and 0.001-0.5% antioxidant, wherein the weight ratio of rasagiline mesylate to cross-linked polyvidone is 1:5-1:15, and the amount of adhesive is adjusted to adjust the final weight percent to 100%, and the release enhancer is one or a combination of several selected from the group consisting of acetylpropionic acid, octanoic acid, and undecenoic acid.

28. 28. The substrate mixture of claim 26 or 27, further comprising absolute ethanol or isopropanol.

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