Rasagiline Mesylate-Containing Transdermal Patch and Method for Preparing the 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 more particularly to a transdermal patch containing rasagiline mesylate and a method for preparing the same. [Background technology]

[0002] Rasagiline is an irreversible selective monoamine oxidase B (MAO-B) inhibitor used to treat central nervous system degenerative Parkinson's disease (PD). Oral formulations of this drug are already marketed in Europe in two formulations: 0.5 mg / day and 1 mg / day. Rasagiline belongs to the category of irreversible monoamine oxidase inhibitors, possessing both strong efficacy and high safety. Oral administration at 20 mg / day for two weeks did not result in serious adverse reactions. Parkinson's patients experience an on-off phenomenon, where during the off-period, their movement is restricted, and they experience mobility difficulties, making oral administration challenging. Transdermal administration can significantly improve patient compliance. Simultaneously, the bioavailability of the oral formulation is relatively low, at only 36%, while transdermal administration directly enters the bloodstream, significantly improving the drug's bioavailability. Currently, rotigotine transdermal patches are already commercially available for the treatment of Parkinson's disease, and they offer clinical advantages over oral administration in terms of improving patient compliance. The development of rasagiline transdermal patches could facilitate administration to Parkinson's patients and improve patient compliance and drug bioavailability. According to data, rasagiline free base is very unstable under weakly basic conditions, whether supported on polyacrylic acid pressure-sensitive adhesive, silicone pressure-sensitive adhesive, or polyvinyl alcohol, as the content of the active ingredient decreases very rapidly, eventually leading to complete decomposition. However, as a mesylate form of rasagiline, rasagiline mesylate maintains its active ingredient content regardless of whether it is supported on polyacrylic acid pressure-sensitive adhesive, silicone pressure-sensitive adhesive, or polyvinyl alcohol, making rasagiline mesylate highly suitable for transdermal patch formulations.

[0003] Transdermal drug delivery systems (TDDS) (also called transdermal therapeutic systems, TTS) are one of the methods of drug absorption through the skin. It is a new administration means that drugs enter the human blood circulation through skin absorption, reach an effective blood drug concentration, and achieve disease treatment or prevention. Transdermal drug delivery systems mainly have the following four advantages: (1) avoiding gastrointestinal irritation and drug degradation, while also avoiding the first-pass effect of the liver, which can improve the bioavailability of drugs; (2) the drug release is stable and sustained, reducing the side effects caused by peak-valley fluctuations; (3) there is no need for frequent administration, improving patient compliance (the elderly, infants, and critically ill patients); (4) the administration is convenient and flexible, and the administration can be immediately stopped when side effects are discovered.

[0004] In summary, manufacturing rasagiline mesylate into a transdermal patch has many advantages and can provide more choices for patients through skin administration.

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

[0006] (2) It is a transdermal patch. The method in the Chinese patent CN101032474B, "Rasagiline transdermal patch for treating or preventing nervous system diseases and its preparation method," can achieve a good transdermal penetration effect, but the drug stability is not good. In this patent, the pH is high, and rasagiline mainly exists in the form of a free base. The R-NH-C≡CH bond between the secondary amine group and the alkynyl group it is linked to is easily cleaved, causing decomposition. Therefore, it is difficult for rasagiline to maintain long-term stability in an environment of basic substrates, especially when it is a free base, the instability becomes more prominent, the drug stability is not good, and it is not suitable for long-term storage.

[0007] The method of transdermally administering lasagiline has many advantages. The defects of existing transdermal administration technologies for lasagiline 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 lasagiline mainly exists in the form of free base, but when lasagiline is in the state of free base, it is very unstable and it is difficult to achieve long-term storage.

Summary of the Invention

[0008] The present invention first provides a transdermal patch containing mesylate lasagiline, and its purpose is to solve the problems of the existing transdermal patch, such as the absorption effect is not ideal, unstable, the drug is likely to precipitate, and it is difficult to achieve long-term storage. The present invention designs a technical solution of loading mesylate lasagiline on a water-insoluble carrier, and first provides a transdermal patch containing mesylate lasagiline, which includes a backing layer, a substrate layer, and a protective layer.

[0009] The first solution is that the substrate layer (in this patent application, it is called the substrate mixture when not coated) contains components with a mass percentage content of 0.5 - 8.0% of mesylate lasagiline, 40 - 80% of an adhesive, 3 - 25% of crosslinked polyvidone, 1 - 5% of a crystallization inhibitor, 1 - 15% of a penetration enhancer, 1 - 10% of a plasticizer, and 0.001 - 0.5% of an antioxidant. The mass ratio of mesylate lasagiline to crosslinked polyvidone is 1:5 - 1:15, and finally, the amount of the adhesive is adjusted so that the total mass percentage reaches 100%. Preferably, the content of mesylate lasagiline is 0.5 - 5.0%.

[0010] The second method is characterized in that the substrate layer (referred to as a substrate mixture in this patent application if not applied) contains components in the following mass percentages: rasagiline mesylate 0.5-5.0%, adhesive 40-80%, crosslinked polyvidone 3-25%, release promoter 0.1-5.0%, penetration promoter 1-15%, plasticizer 0.5-10%, and antioxidant 0.001-0.5%, and the mass ratio of rasagiline mesylate to crosslinked polyvidone is 1:5-1:15, and the amount of adhesive is adjusted to finally reach 100% mass percentage.

[0011] The beneficial effects of adopting the above technical proposal are as follows: The adhesives currently selected and used in TDDS administration systems are mainly acrylate-based, organic polysiloxane-based, and hot-melt adhesive-based adhesives. All of these adhesives are organic solvent-based dissolution systems and are mainly used for transdermal patches of lipid-soluble drugs, but there is a problem in that rasagiline mesylate and solvent-based adhesives are incompatible. The present invention creatively uses cross-linked polyvidone, a drug carrier normally used to carry lipid-soluble or water-insoluble drugs, to carry rasagiline mesylate, a water-soluble drug. Through the synergistic action of rasagiline mesylate, the drug carrier, and a crystallization inhibitor, a hydrogen bond complex is formed, allowing rasagiline mesylate to be stably present on the drug carrier in an amorphous state. The prepared patch does not exhibit crystallization, and rasagiline exists in the form of a salt, preventing instability of the formulation. This type of combination method is the first to be described for transdermal patches.

[0012] In particular, the inventors, through experimental exploration, discovered that when the drug load is low (<0.5%), rasagiline mesylate does not precipitate in large quantities in combinations without PVPP, because the system has a certain degree of solubility for the drug. However, when the rasagiline mesylate content exceeds 0.50%, large quantities of crystals precipitate. Considering the drugability of transdermal patch drugs, even trace amounts of crystal precipitation can have a certain effect on drug dissolution, release, and penetration, thus affecting the drug's efficacy. Therefore, low drug loads and a certain proportion of crystallization make it difficult to formulate the drug, and the crystallization problem must be solved by increasing the drug load. Adding PVPP allows for an increase in drug load without crystallization. Experimental exploration revealed that the maximum drug load in the system is less than 5.0% by mass of rasagiline mesylate, and that too much makes the process difficult to implement. Further experiments also found that the system exhibits relatively good druggability when the mass ratio of rasagiline mesylate to cross-linked polyvidone is between 1:5 and 1:15.

[0013] Therefore, the rasagiline mesylate-containing transdermal patch formulation proposed by the present invention allows for the preparation of a patch with a high drug load, which does not precipitate even after long-term storage and meets druggability requirements. Tests have shown that, when the substrate layer thickness of the final prepared patch is appropriate, the active drug content per unit area is 0.058 to 0.565 mg / cm² in terms of rasagiline free base. 2 This resulted in the salt-type drug being supported in an organic solvent pressure-sensitive adhesive system at a relatively high concentration without crystallization.

[0014] Furthermore, the formulation of the present invention overcomes the problems that inevitably arise when applying a patch to the patient's epidermis, such as skin discomfort, redness, and swelling, which are always caused by adjusting the pH value using inorganic salts, inorganic bases, or organic bases in the CN101032474B proposal (although CN101032474B emphasizes adjusting the pH to an appropriate range, adding inorganic salts, inorganic bases, or organic bases inevitably irritates the skin and causes discomfort).

[0015] Drugs can be accurately, stably, and continuously released and delivered without the need for release control membranes. The transdermal effect is ideal, with a 24-hour cumulative penetration of 20-100 μg / cm³. 2 It is possible to reach this.

[0016] It offers an excellent user experience, as the drug carrier is insoluble in water and ethanol, exists in the formulation in the form of particles, and prevents stickiness, adhesive residue problems, and impacts on user comfort caused by the inclusion of a high proportion of polymer crystallization inhibitors.

[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 monocaprilate, 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 monocaprilate or polyglycerol fatty acid ester.

[0023] Preferably, the plasticizer is one or a combination of several selected from 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). The preferred option is the backing layer, SCOTCHPAK TM 9738, SCOTCHPAK TM 9730, SCOTCHPAK TM It is one of the options selected from 1109.

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

[0027] In the first solution, Preferably, the substrate layer further contains a component with a mass percentage content of 0.1 - 5.0% of a release accelerator.

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

[0029] In the second solution, Preferably, the substrate layer further contains a component with a mass percentage content of 1 - 5% of a crystallization inhibitor.

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

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

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

[0033] In the first and second solutions, The release accelerator is one or a combination of several selected from acetylpropionic acid, octanoic acid, undecenoic acid, and preferably it is acetylpropionic acid.

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

[0035] The first method, The present invention A strip 1 prepares a drug-containing adhesive layer (substrate layer; in this patent application, referred to as a substrate mixture if not applied) by measuring 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, dissolving them in a solvent, mixing and stirring until the solid is completely dissolved and a homogeneous solution is obtained, adding 3-25% crosslinked polyvidone to the homogeneous solution, premixing, allowing it to swell sufficiently, and then homogenizing it to obtain a white milky liquid, adding 40-80% adhesive to the white milky liquid, and mixing and stirring until homogeneous to obtain an intermediate solution, and

[0036] The intermediate solution is applied to a release film (protective layer) to obtain a wet film with a thickness of 100-500 μm, and then dried to obtain a dry substrate with a thickness of 20-250 μm. This is a strip 2 that removes the solvent by coating and drying.

[0037] The backing film (backing layer) is laminated with the above-mentioned dried substrate to form a composite, and the laminate composite and cutting tape 3 is further cut into patches.

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

[0039] Method two, The present invention A strip 1 prepares a drug-containing substrate layer (referred to as a substrate mixture in this patent application if not applied) by measuring 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, dissolving them in a solvent, mixing and stirring until the solid is completely dissolved and a homogeneous solution is obtained, adding 3-25% crosslinked polyvidone to the homogeneous solution, pre-mixing and allowing it to swell sufficiently, then homogenizing to obtain a white milky liquid, adding 40-80% adhesive to the white milky liquid, and mixing and stirring until homogeneous to obtain an intermediate solution, and

[0040] The intermediate solution is applied to a protective layer, resulting in a wet film thickness of 100-500 μm, and then dried to obtain a dry substrate with a dry film thickness of 20-250 μm. This process removes the solvent.

[0041] The backing layer is laminated with the above-mentioned dried substrate to form a composite, and the laminate composite and cutting tape 3 is further cut into patches.

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

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

[0044] Rasagiline mesylate, the drug carrier cross-linked polyvidone, and the crystallization inhibitor work together to form a hydrogen bond complex, allowing rasagiline mesylate to be present in an amorphous state on the drug carrier. The prepared patch does not exhibit crystallization, and rasagiline is present in salt form, preventing instability of the formulation.

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

[0046] Preferably, the solvent in Stap 1 is selected from anhydrous ethanol. Preferably, the drying of Stap 2 is carried out using a three-stage drying method, with the first stage being drying at 20-30°C for 2-10 minutes (preferably at 20-25°C for 2-10 minutes), the second stage being drying at 45-65°C for 2-10 minutes, and the third stage being drying at 65-85°C for 2-10 minutes.

[0047] In Method 1, Preferably, the substrate layer further contains a component with a mass percentage content of 0.1 to 5.0% of a release promoter.

[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 two, The substrate layer further contains a component with a crystallization inhibitor content of 1-5% by mass.

[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 methods 1 and 2, it is preferable that the usable area after cutting is 3 cm². 2 ~30cm 2 That is the case.

[0054] In particular, unless otherwise specified, measurement results from measuring instruments are subject to unavoidable errors, and therefore all numerical ranges in this specification have an error of ±10%. [Brief explanation of the drawing]

[0055] [Figure 1] This is a cross-sectional structural diagram of the transdermal patch according to the present invention. [Figure 2] This is a plot of the Qt relationship for the formulations of Examples 3 to 7 in the present invention. [Figure 3] This is a plot of the Qt relationship for the formulations of Examples 8-9 in the present invention. [Figure 4] The images are polarized microscope photographs taken after placing patches prepared according to the formulations of Examples 1' to 3' of the present invention. [Modes for carrying out the invention]

[0056] The preferred embodiments described below are illustrative only, and those skilled in the art may conceive of other obvious modifications. The basic principles of the present invention as defined below can be applied to other embodiments, modifications, improvements, equivalents, and other technical applications that do not depart from the spirit and scope of the present invention.

[0057] In the following description, Examples 1 and 2 compare formulations containing PVPP (cross-linked polyvidone) with those without PVPP, with the purpose of explaining that PVPP can support rasagiline mesylate, a water-soluble drug.

[0058] Examples 3-7 are IVPT (In Vitro Permeation Testing) studies that screen formulations without penetration enhancers and formulations containing penetration enhancers with HLB values ​​of 1-5 (HLB: Hydrophilic Lipophilic Balance is an abbreviation for hydrophilic-lipophilic balance). The necessity of using penetration enhancers and the reasons why penetration enhancers with HLB values ​​of 3-5 are preferred will be further explained. The IVPT results for Examples 3-7 are shown in Figure 2, and the equation for penetration amount (Q)-time (t) is shown in Table 1.

[0059] Examples 8-9 involved further combining different penetration enhancers and plasticizers with HLB (Hydrophile Lipophilic Balance, an abbreviation for hydrophilic-lipophilic balance value) values ​​of 3-5, and were optimized and screened using IVRT (In Vitro Release Testing) and IVPT (In Vitro Permeation Testing, an abbreviation for extracorporeal release testing). The IVPT results for Examples 8-9 are shown in Figure 3, and the equation for permeation amount (Q)-time (t) is shown in Table 2.

[0060] In this invention, the extracorporeal emission study (IVRT) was conducted using "Chinese Pharmacopoeia (2020 Edition) 0931, Method 4 (Stirred Paddle Dish Method)". The cumulative release amount within a certain sampling time was calculated using an emission meter and high-performance liquid chromatography, and the relationship between the release rate (%) of rasagiline and time (t) was plotted. The proposed implementation of IVRT is as follows.

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

[0062] Media volume / temperature / rotation speed / sample volume: 900 mL, 32 ± 0.5 °C, 50 r / min, 3 samples / cycle.

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

[0064] Chromatography conditions: Chromatography column: Agilent Zorbax SB-C18 4.6×250mm, 5μm; Mobile phase: 10mM KH2PO4:ACN=80:20; Flow rate: 1.0mL / min; Column temperature: 40℃; Detection wavelength: 210nm; Injection volume: 50μl; Sampling time: 6min.

[0065] In extracorporeal permeation studies (IVPT), ​​the permeability of rasagiline mesylate is evaluated using Franz diffusion cells (an in vitro transdermal experimental system) and Bama pig skin. Using 0.01% gentamicin sulfate (pH 7.4 PBS) as the receptor solution, the content of rasagiline at different sampling points in the receptor cells is measured by high-performance liquid chromatography, the cumulative permeation amount of rasagiline is calculated, and a plot of the cumulative permeation amount (Q)-time (t) relationship is drawn.

[0066] Furthermore, to demonstrate that the patch has relatively good performance, the transdermal patches prepared using the formulation and process of [Example 9] were further tested for adhesion and peelability.

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

[0068] Example 1 JPEG0007895674000001.jpg65148

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

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

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

[0072] After the patches prepared using the above formulation and process were left at room temperature for 3 days, a large amount of crystals precipitated.

[0073] Example 2 JPEG0007895674000002.jpg73148

[0074] Tape 1: Prepare the drug-containing adhesive layer (substrate layer). (1) Mix and stir rasagiline mesylate, triethyl citrate, propylene glycol monocaprilate, polyglycerol oleate, and anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

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

[0076] Tape 3: Laminate, composite, and cut. SCOTCHPAK TM The 9738 backing film (backing layer) is laminated with the above-mentioned dry substrate to form a composite, and then further laminated for 10 cm 2 Disconnect to the patch.

[0077] Patches prepared using the above formulation and process showed no crystal precipitation after 60 days under four different conditions: room temperature, high temperature (40°C), refrigeration (4°C), and freezing (-18°C). This indicates that PVPP can support rasagiline mesylate, a water-soluble drug.

[0078] Examples 3-7 examine IVPT by preparing formulations without a penetration enhancer and containing a penetration enhancer with an HLB value of 1-5, further explaining the necessity of a penetration enhancer and the reasons for selecting a penetration enhancer with an HLB value of 3-5. The equations for permeation amount (Q)-time (t) for Examples 3-7 are shown in Table 1, and the IVPT plots are shown in Figure 2.

[0079] Example 3: Without a penetration enhancer JPEG0007895674000003.jpg73148

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

[0081] Step 2: Apply and remove the solvent by drying. Use SCOTCHPAK for the intermediate solution. TM The 1022 release film (protective layer) is coated to a wet film thickness of 300 μm, and then drying is performed. A three-stage drying method is used: drying at 20°C for 10 min, drying at 60°C for 10 min, and drying at 75°C for 10 min. A dried substrate is obtained with a thickness of 120 μm.

[0082] Tape 3: Laminate, composite, and cut. SCOTCHPAK TM The 9730 backing film (backing layer) is laminated with the above-mentioned dry substrate to form a composite, and then further laminated for 10 cm 2 Cut to the patch. The IVPT results are shown in Figure 2.

[0083] Example 4 Penetration enhancer: Glycerin monolinoleate JPEG0007895674000004.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 anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

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

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

[0087] Example 5 Penetration enhancer: Glycerin monooleate JPEG0007895674000005.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 anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-4098 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

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

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

[0091] Example 6 Penetration enhancer: Polyglycerol oleate JPEG0007895674000006.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 anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

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

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

[0095] Example 7 Penetration accelerator: Propylene glycol monocaprilate JPEG0007895674000007.jpg82150

[0096] Tape 1: Prepare the drug-containing adhesive layer (substrate layer). (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, propylene glycol monocaprilate, and anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2287 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

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

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

[0099] Table 1: Qt equations for formulations of Examples 3-7 JPEG0007895674000008.jpg87170

[0100] Here, J represents the penetration rate. (Note: R 2 This parameter evaluates the fitting effect of a linear regression model. A value of 1 indicates that all data points in the model lie perfectly on the regression line. A value closer to 1 indicates a better fitting effect and higher model fit, while a value closer to 0 indicates a worse fitting effect and lower model fit.

[0101] Analysis of results from Examples 3-7: Penetration 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 monocaprilate C90 (HLB=5) (J=1.5849) < Polyglycerol oleate CC497 (HLB=3) (J=1.9380). All formulations with added penetration enhancers showed improvement in J values ​​compared to formulations without the enhancer, to a different degree. Formulations with added propylene glycol monocaprilate and polyglycerol fatty acid esters showed increased penetration rates of 10 and 13 times, respectively, compared to formulations without the enhancer. Therefore, penetration enhancers with an HLB of 3-5 have a better penetration-enhancing effect 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 values ​​of 3-5 and the plasticizer triethyl citrate to control the delivery rate.

[0103] Table 2 shows the extracorporeal release of IVRT in Examples 8-9. Figure 3 shows IVPT. Table 3 shows the transmission rate (Q)-time (t) equation.

[0104] Example 8: Combination of penetration enhancers JPEG0007895674000009.jpg89148

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

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

[0107] Tape 3: Laminate, composite, and cut. SCOTCHPAK TM The 9738 backing film (backing layer) is laminated with the above-mentioned dry substrate to form a composite, and then further laminated for 10 cm 2 Disconnect to the patch

[0108] Example 9: Combination of penetration enhancers JPEG0007895674000010.jpg89148

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

[0110] Step 2: Apply and remove the solvent by drying. Use SCOTCHPAK for the intermediate solution. TM The 1022 release film (protective layer) is coated to a wet film thickness of 300 μm, and then drying is performed. A three-stage drying method is used: drying at 20°C for 10 min, drying at 60°C for 10 min, and drying at 75°C for 10 min. A dried substrate is obtained with a thickness of 120 μm.

[0111] Tape 3: Laminate, composite, and cut. SCOTCHPAKTM The 9738 backing film (backing layer) is laminated with the above-mentioned dry substrate to form a composite, and then further laminated for 10 cm 2 Disconnect to the patch.

[0112] Table 2 Results of IVRT in Examples 8-9 JPEG0007895674000011.jpg74148

[0113] Table 3 Relationship between cumulative permeation (Q) and time (t) in Examples 8-9 JPEG0007895674000012.jpg50149

[0114] Analysis of results from Examples 8-9: A comparison of the IVRTs in [Example 8] and [Example 9] revealed that the IVRT release behavior of the formulations was almost identical, with [Example 9] showing a slightly higher release rate than [Example 8]. It can be inferred that penetration enhancers with lower HLB values ​​may be more advantageous for drug release. As can be seen by comparing [Example 8] and [Example 9], under conditions where the total amount of penetration enhancers (6%) is the same, the penetration rate of 5% plasticizer is faster than that of 4% plasticizer. Considering the conclusion that [Example 9] shows a slightly higher release rate than [Example 8], it can be inferred that increasing the proportion of plasticizer increases drug release, resulting in a larger skin drug concentration gradient within the same time, which is more advantageous for penetration progression according to Fick's Law. Therefore, formulations with a larger release rate may also have a correspondingly faster penetration rate.

[0115] Furthermore, to demonstrate that the patch has relatively good performance, the following parameters were further tested on the transdermal patch prepared using the formulation and process of [Example 9].

[0116] Peeling force: The 180° peeling test method was adopted using the test apparatus specified in the section "Measurement of Peeling Strength" of General Rule 0952, Part 3, of the 2020 edition of the "Chinese Pharmacopoeia". The procedure was repeated, and the average value of 6 results was calculated to be 1.15 N / 50 mm.

[0117] Finally, to further demonstrate the good stability of the patch, further stability tests were performed on the transdermal patches prepared using the formulation and process of [Example 9]. The results are shown in Table 4.

[0118] Table 4: Changes in active ingredient content in transdermal patches under different study conditions JPEG0007895674000013.jpg17149

[0119] The above examples are specific examples corresponding to Solution 1 and Method 1, and the following examples are specific examples corresponding to Solution 2 and Method 2.

[0120] In the following description, Examples 1' to 6' compare formulations containing cross-linked polyvidone with those not containing it, with the purpose of explaining that cross-linked polyvidone can carry the water-soluble drug rasagiline mesylate, that the final drug load in the system is 0.5 to 5.0% rasagiline mesylate (higher amounts make the process difficult to implement and industrial production impossible), 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 (In Vitro Permeation Testing) results of formulations without permeation enhancers and formulations containing permeation enhancers with different HLB values ​​(HLB: Hydrophobic Balance), further explaining the necessity of using permeation enhancers and why polyglycerol fatty acid esters are preferred. The permeation rate (Q)–time (t) equations for Examples 7' to 11' are shown in Table 5.

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

[0123] Examples 15' to 17' further illustrate how different combinations of penetration enhancers and release enhancers can be used to investigate IVPT and achieve a controllable drug delivery rate. The results for IVRT and IVPT are shown in Tables 7 and 8.

[0124] In this invention, the extracorporeal emission study (IVRT) will adopt the fourth method (stirred paddle dish method) described in 0931 of the "Chinese Pharmacopoeia" (2020 edition). The cumulative release amount within a certain sampling time will be calculated using an emission meter and high-performance liquid chromatography, and the relationship between the release rate (%) of rasagiline and time (t) will be plotted. The proposed implementation of the IVRT is as follows.

[0125] Release medium: pH 4.5 acetate buffer.

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

[0127] Chromatography conditions: Chromatography column: Agilent Zorbax SB-C18 4.6×250mm, 5μm; Mobile phase: 10mM KH2PO4:ACN=80:20; Flow rate: 1.0mL / min; Column temperature: 40℃; Detection wavelength: 210nm; Injection volume: 50μl; Sampling time: 6min.

[0128] In extracorporeal permeation studies (IVPT), ​​the penetration capacity of rasagiline mesylate was evaluated using Franz diffusion cells (an in vitro transdermal experimental system) and Bama pig skin. The receptor solution was 0.01% gentamicin sulfate (pH 7.4 PBS), and the rasagiline content in the receptor cells was measured at different sampling points using high-performance liquid chromatography. The cumulative permeation of rasagiline was calculated, and the relationship between cumulative permeation (Q) and time (t) was plotted.

[0129] Furthermore, to demonstrate that the patch has relatively good performance, the adhesive strength and peelability of the transdermal patch prepared using the formulation and process of Example 15' were further tested, and the results are shown in Table 9.

[0130] Finally, to further demonstrate the good stability of the patch, further stability tests were performed on the transdermal patches prepared using the formulation and process of Example 15'. The results are shown in Table 10.

[0131] Examples 1'-6' The main invention of this present invention is to obtain a patch with a high drug load by loading the water-soluble drug rasagiline mesylate by adding PVPP. Therefore, experiments are designed to explore the final formulation by considering three variables: whether or not 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. JPEG0007895674000014.jpg165170

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

[0134] Step 2: Apply and remove the solvent by drying. Use SCOTCHPAK for the intermediate solution. TM The 2504 protective layer was coated to create a wet film with a thickness of 300 μm, after which drying was performed. A three-stage drying method was employed: drying at 30°C for 8 minutes, drying at 65°C for 8 minutes, and drying at 80°C for 10 minutes. A dried substrate was obtained with a thickness of 120 μm.

[0135] Tape 3: Laminate, composite, and cut. SCOTCHPAK TM The 1109 backing layer is laminated with the above-mentioned dry substrate to form a composite, and then further laminated for 10 cm. 2 Disconnect to the patch.

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

[0137] By comparing Example 1' and Example 3', it was proven that crystallization occurs regardless of whether the drug load is high (2%) or low (0.1%), and in the absence of PVPP. Quantitative analysis and statistics were performed on the amount of crystallization (see Figure 4). The crystallization area is calculated as a percentage of the total area. Examples 4' to 6' show no crystallization observed, comparing the micromorphology observed under unpolarized light with that observed under polarized light.

[0138] Examples 4' to 6' demonstrate that crystallization can be prevented by adding PVPP. At the same time, by exploring the appropriate ratio of PVPP to the drug, the maximum drug load in this system is 5.0 or less.

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

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

[0141] Example 7': Without penetration enhancer JPEG0007895674000015.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 anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

[0143] Step 2: Apply and remove the solvent by drying. Use SCOTCHPAK for the intermediate solution. TM The 1022 protective layer was coated to create a wet film with a thickness of 300 μm, after which drying was performed. A three-stage drying method was employed: drying at 25°C for 10 minutes, drying at 60°C for 10 minutes, and drying at 75°C for 10 minutes. A dried substrate was obtained with a thickness of 120 μm.

[0144] Tape 3: Laminate, composite, and cut. SCOTCHPAK TM The 9738 backing layer is laminated with the above-mentioned dry substrate to form a composite, and then further laminated for 10 cm 2 Disconnect to the patch.

[0145] Example 8' Penetration enhancer: Glycerin monolinoleate JPEG0007895674000016.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 anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

[0147] Step 2: Apply and remove the solvent by drying. Use SCOTCHPAK for the intermediate solution. TM The 1022 protective layer was coated to create a wet film with a thickness of 300 μm, after which drying was performed. A three-stage drying method was employed: drying at 25°C for 10 minutes, drying at 60°C for 10 minutes, and drying at 75°C for 10 minutes. A dried substrate was obtained with a thickness of 120 μm.

[0148] Tape 3: Laminate, composite, and cut. SCOTCHPAK TM The 9738 backing film is laminated with the above-mentioned dry substrate to form a composite, and then further laminated to 10 cm 2 Disconnect to the patch.

[0149] Example 9' Penetration enhancer: Glycerin monooleate JPEG0007895674000017.jpg81148

[0150] Tape 1: Prepare the drug-containing adhesive layer (substrate layer). (1) Mix and stir rasagiline mesylate, vitamin E, triethyl citrate, glycerol monooleate, acetylpropionic acid, and anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

[0151] Step 2: Apply and remove the solvent by drying. Use SCOTCHPAK for the intermediate solution. TM The 1022 protective layer was coated to create a wet film with a thickness of 300 μm, after which drying was performed. A three-stage drying method was employed: drying at 25°C for 10 minutes, drying at 60°C for 10 minutes, and drying at 75°C for 10 minutes. A dried substrate was obtained with a thickness of 120 μm.

[0152] Tape 3: Laminate, composite, and cut. SCOTCHPAK TM The 9738 backing layer is laminated with the above-mentioned dry substrate to form a composite, and then further laminated for 10 cm 2 Disconnect to the patch.

[0153] Example 10' Penetration enhancer: Polyglycerol oleate JPEG0007895674000018.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 anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

[0155] Step 2: Apply and remove the solvent by drying. Use SCOTCHPAK for the intermediate solution. TM The 1022 protective layer was coated to create a wet film with a thickness of 300 μm, after which drying was performed. A three-stage drying method was employed: drying at 25°C for 10 minutes, drying at 60°C for 10 minutes, and drying at 75°C for 10 minutes. A dried substrate was obtained with a thickness of 120 μm.

[0156] Tape 3: Laminate, composite, and cut. SCOTCHPAK TM The 9738 backing layer is laminated with the above-mentioned dry substrate to form a composite, and then further laminated for 10 cm 2 Disconnect to the patch.

[0157] Example 11' Penetration accelerator: Propylene glycol monocaprilate JPEG0007895674000019.jpg81148

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

[0159] Step 2: Apply and remove the solvent by drying. Use SCOTCHPAK for the intermediate solution. TM The 1022 protective layer was coated to create a wet film with a thickness of 300 μm, after which drying was performed. A three-stage drying method was employed: drying at 25°C for 10 minutes, drying at 60°C for 10 minutes, and drying at 75°C for 10 minutes. A dried substrate was obtained with a thickness of 120 μm.

[0160] Tape 3: Laminate, composite, and cut. SCOTCHPAK TMThe 9738 backing layer is laminated with the above-mentioned dry substrate to form a composite, and then further laminated for 10 cm 2 Disconnect to the patch.

[0161] Table 5 Qt equations for formulations of Examples 7'~11' JPEG0007895674000020.jpg87170

[0162] Here, J represents the penetration rate. (Note: R 2 This parameter evaluates the fitting effect of a linear regression model. A value of 1 indicates that all data points in the model lie perfectly on the regression line. A value closer to 1 indicates a better fitting effect and higher model fit, while a value closer to 0 indicates a worse fitting effect and lower model fit.

[0163] Analysis of results for Examples 7'-11': All formulations containing penetration enhancers showed varying degrees of improvement in J values ​​compared to formulations without penetration enhancers. Among these, polyglycerol fatty acid esters showed the best penetration-enhancing effect, making it preferable to use polyglycerol fatty acid esters as the penetration enhancer for rasagiline mesylate patches.

[0164] Examples 12' to 14' compare and discuss IVRT formulations containing acetylpropionic acid, octanoic acid, and undecenoic acid, further explaining why acetylpropionic acid is preferable as a release enhancer. The IVRT results are shown in Table 6.

[0165] Example 12' Release promoter: Acetylpropionic acid JPEG0007895674000021.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 anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

[0167] Strip 2: Apply and remove the solvent by drying. The intermediate solution is applied to the 75E-0010BD protective layer, resulting in a wet film thickness of 300 μm, after which drying is performed. A three-stage drying method is used: drying at 25°C for 10 min, drying at 65°C for 8 min, and drying at 80°C for 8 min. A dried substrate is obtained with a thickness of 120 μm.

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

[0169] Example 13' Release promoter: Octanoic acid JPEG0007895674000022.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 anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

[0171] Strip 2: Apply and remove the solvent by drying. The intermediate solution is applied to the 75E-0010BD protective layer, resulting in a wet film thickness of 300 μm, after which drying is performed. A three-stage drying method is used: drying at 25°C for 10 min, drying at 65°C for 8 min, and drying at 80°C for 8 min. A dried substrate is obtained with a thickness of 120 μm.

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

[0173] Example 14' Release promoter: Undecenoic acid JPEG0007895674000023.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 anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

[0175] Strip 2: Apply and remove the solvent by drying. The intermediate solution is applied to the 75E-0010BD protective layer, resulting in a wet film thickness of 300 μm, after which drying is performed. A three-stage drying method is used: drying at 25°C for 10 min, drying at 65°C for 8 min, and drying at 80°C for 8 min. A dried substrate is obtained with a thickness of 120 μm.

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

[0177] Table 6 IVRT of Examples 12'–14' JPEG0007895674000024.jpg72170

[0178] Analysis of results for Examples 12' to 14': Before 2 hours, the release rates were in the order of 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 initial stages of release.

[0179] Examples 15' to 17' further illustrate how IVPT can be achieved by considering different ratios of penetration enhancers and release enhancers to realize a controllable drug delivery rate. The results for IVRT and IVPT are shown in Tables 7 and 8.

[0180] Example 15' JPEG0007895674000025.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 anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

[0182] Strip 2: Apply and remove the solvent by drying. The intermediate solution is applied to the 75E-0010BD protective layer, resulting in a wet film thickness of 300 μm, after which drying is performed. A three-stage drying method is used: drying at 25°C for 10 min, drying at 60°C for 10 min, and drying at 80°C for 8 min. A dried substrate is obtained with a thickness of 120 μm.

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

[0184] Example 16' JPEG0007895674000026.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 anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

[0186] Strip 2: Apply and remove the solvent by drying. The intermediate solution is applied to the 75E-0010BD protective layer, resulting in a wet film thickness of 300 μm, after which drying is performed. A three-stage drying method is used: drying at 25°C for 10 min, drying at 60°C for 10 min, and drying at 80°C for 8 min. A dried substrate is obtained with a thickness of 120 μm.

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

[0188] Example 17' JPEG0007895674000027.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 anhydrous ethanol until all solids are completely dissolved to obtain a clear and homogeneous solution. (2) Add cross-linked polyvidone to the above solution, pre-mix and stir uniformly, then homogenize to obtain a white milky liquid. (3) Add DURO-TAK387-2052 to the above liquid and mix and stir until homogenized to obtain an intermediate solution.

[0190] Strip 2: Apply and remove the solvent by drying. The intermediate solution is applied to the 75E-0010BD protective layer, resulting in a wet film thickness of 300 μm, after which drying is performed. A three-stage drying method is used: drying at 25°C for 10 min, drying at 60°C for 10 min, and drying at 80°C for 8 min. A dried substrate is obtained with a thickness of 120 μm.

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

[0192] Table 7 IVRT of Examples 15'-17' JPEG0007895674000028.jpg71170

[0193] Table 8 Relationship between cumulative permeation (Q) and time (t) for Examples 15' to 17' JPEG0007895674000029.jpg65149

[0194] Analysis of results in Examples 15'-17': In Examples 15'-17', the release rate increased with increasing acetylpropionic acid, and the penetration rate gradually decreased with decreasing polyglycerol fatty acid ester. The release-promoting effect of acetylpropionic acid and the penetration-promoting effect of polyglycerol fatty acid ester will be further explained. By adjusting the amounts of the release promoter and the penetration promoter, the release rate and penetration rate of the drug can be controlled.

[0195] Furthermore, to further demonstrate that the patch has relatively good performance, the peel strength and adhesion durability of the transdermal patch prepared using the formulation and process of Example 15' were further tested.

[0196] Finally, to further demonstrate the good stability of the patch, further stability tests were performed on the transdermal patches prepared using the formulation and process of Example 15'. The results are shown in Table 9.

[0197] Table 9 Results of peel strength and adhesion durability tests for Example 15' JPEG0007895674000030.jpg18150

[0198] Finally, to further demonstrate the good stability of the patch, further stability tests were performed on the transdermal patches prepared using the formulation and process of Example 15'. The results are shown in Table 10.

[0199] Table 10: Changes in active ingredient content in transdermal patches under different study conditions. JPEG0007895674000031.jpg32170

[0200] Those skilled in the art should understand that in the process of preparing a transdermal patch, the product obtained in the process of preparing the patch 1, i.e., the drug-containing adhesive layer (substrate layer, substrate mixture), is an intermediate product (drug-containing adhesive layer (substrate layer, substrate mixture)). In order to facilitate stirring and the transition to subsequent preparation processes, an organic solvent (such as ethanol or isopropanol, which is an easily evaporable and easily removed organic solvent) may be added during this process to aid dissolution, dilute, and reduce the viscosity of the mixture. Alternatively, an organic solvent (for example, 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 this application, ethanol, an organic solvent, was added based on the understanding that adding an organic solvent to aid dissolution, dilute, and reduce the viscosity of the mixture facilitates stirring and the transition to subsequent preparation processes.

[0201] Those skilled in the art should understand that, through the process of removing the solvent by drying in Tape 2, the final prepared transdermal patch should be free of organic solvents or retain only very small amounts of organic solvents that meet pharmacopoeial requirements or pharmaceutical quality requirements.

[0202] Those skilled in the art should understand that the embodiments of the present invention described above are illustrative and not limiting. The object of the present invention has been fully and effectively achieved. The principles of the function and structure of the present invention have already been shown and explained in the embodiments, and embodiments of the present invention may be modified in any way that does not depart from the above principles.

Claims

1. A rasagiline mesylate-containing transdermal patch comprising a backing layer, a substrate layer, and a protective layer, wherein the substrate layer contains components in the following mass percentage amounts: 0.5-5.0% rasagiline mesylate, 40-80% adhesive, 3-25% crosslinked polyvidone, 1-5% crystallization inhibitor, 1-15% penetration enhancer, 1-10% plasticizer, and 0.001-0.5% antioxidant, wherein the mass ratio of rasagiline mesylate to crosslinked polyvidone is 1:5-1:15, and the amount of adhesive is adjusted to finally adjust to 100% mass percentage, thereby further comprising components in the substrate layer in the following mass percentage amount: 0.1-5.0% release enhancer, wherein the release enhancer is one or a combination of several selected from acetylpropionic acid, octanoic acid, and undecenoic acid.

2. A rasagiline mesylate-containing transdermal patch comprising a backing layer, a substrate layer, and a protective layer, wherein the substrate layer contains components in the following mass percentage amounts: 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 mass ratio of rasagiline mesylate to cross-linked polyvidone is 1:5-1:15, the amount of adhesive is adjusted to finally reach 100% mass percentage, and the release enhancer is one or a combination of several selected from acetylpropionic acid, octanoic acid, and undecenoic acid.

3. The rasagiline mesylate-containing transdermal patch according to claim 1 or 2, characterized in that the release enhancer is acetylpropionic acid.

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

5.

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

5.

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

4.

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

10.

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

15.

9. The rasagiline mesylate-containing transdermal patch according to claim 1 or 2, characterized in that the adhesive is selected from acrylate pressure-sensitive adhesives.

10. The rasagiline mesylate-containing transdermal patch according to claim 9, characterized in that 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.

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

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

13. The 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 monocaprilate, polyglycerol fatty acid ester, glycerin monooleate, glycerin monolinoleate, glycerin monostearate, span 80, and span 60.

14. The rasagiline mesylate-containing transdermal patch according to claim 13, characterized in that the penetration enhancer is selected from propylene glycol monocaprilate or polyglycerol fatty acid ester.

15. The rasagiline mesylate-containing transdermal patch according to claim 1 or 2, characterized in that the plasticizer is one or a combination of several selected from triethyl citrate, glycerin triacetate, and dibutylphthalate.

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

17. The rasagiline mesylate-containing transdermal patch 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 aforementioned backing layer is SCOTCHPAK ＴＭ 9738, SCOTCHPAK ＴＭ 9730, SCOTCHPAK ＴＭ It is one of the types selected from 1109, wherein the protective layer is SCOTCHPAK ＴＭ 1022, SCOTCHPAK ＴＭ A transdermal patch containing rasagiline mesylate according to claim 1 or 2, characterized in that it is one selected from 2504 and 75E-0010BD.

20. Step 1 involves weighing 0.5-5.0% rasagiline mesylate, 1-5% crystallization inhibitor, 1-15% penetration enhancer, 0.1-5.0% release enhancer, 1-10% plasticizer, and 0.001-0.5% antioxidant, dissolving them in a solvent, and mixing and stirring until all solids are completely dissolved to obtain a homogeneous solution. Step 2 involves adding 3-25% crosslinked polyvidone to the homogeneous solution, pre-mixing, allowing it to swell sufficiently, and then homogenizing it to obtain a white milky liquid. Step 3 involves adding 40-80% adhesive to the white milky liquid and mixing and stirring until homogeneous to obtain an intermediate solution. Step 2 involves coating the intermediate solution onto a protective layer, resulting in a wet film thickness of 100 to 500 μm, followed by drying to obtain a dried substrate, and removing the solvent by coating and drying, resulting in a dry film thickness of 20 to 250 μm. Step 3 involves laminating and cutting the backing layer with the above-mentioned dried substrate to create a composite, and then cutting it into patches. Includes, A method for preparing a rasagiline mesylate-containing transdermal patch, characterized in that the release promoter 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 to finally achieve 100% mass percentage.

21. Step 1 involves weighing 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, dissolving them in a solvent, and mixing and stirring until all solids are completely dissolved to obtain a homogeneous solution. Step 2 involves adding 3-25% crosslinked polyvidone to the homogeneous solution, pre-mixing, allowing it to swell sufficiently, and then homogenizing it to obtain a white milky liquid. Step 3 involves adding 40-80% adhesive to the white milky liquid and mixing and stirring until homogeneous to obtain an intermediate solution. Step 2 involves coating the intermediate solution onto a protective layer, resulting in a wet film thickness of 100 to 500 μm, followed by drying to obtain a dried substrate with a dry film thickness of 20 to 250 μm, thereby removing the solvent through coating and drying. Step 3 involves laminating and cutting the backing layer with the above-mentioned dried substrate to create a composite, and then cutting it into patches. Includes, A method for preparing a rasagiline mesylate-containing transdermal patch, characterized in that the release promoter 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 to finally achieve 100% mass percentage.

22. The preparation method according to claim 20 or 21, characterized in that the solvent in step 1 is one or a combination of both selected from anhydrous ethanol or isopropanol.

23. The preparation method according to claim 22, characterized in that the solvent in step 1 is selected from anhydrous ethanol.

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

25. The preparation method according to claim 24, characterized in that the first drying step in step 2 is performed at 20 to 25°C for 2 to 10 minutes.

26. A substrate mixture for preparing a rasagiline mesylate transdermal patch, comprising components in the following mass percentage content: rasagiline mesylate 0.5-5.0%, adhesive 40-80%, cross-linked polyvidone 3-25%, crystallization inhibitor 1-5%, penetration enhancer 1-15%, release enhancer 0.1-5.0%, plasticizer 1-10%, and antioxidant 0.001-0.5%, wherein the mass ratio of rasagiline mesylate to cross-linked polyvidone is 1:5-1:15, and the amount of adhesive is adjusted to finally reach 100% mass percentage, characterized in that the release enhancer is one or a combination of several selected from acetylpropionic acid, octanoic acid, and undecenoic acid.

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

28. The substrate mixture according to claim 26 or 27, further comprising anhydrous ethanol or isopropanol.

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