Memantine external transdermal patch and preparation method thereof

Abstract

The invention discloses a memantine external transdermal patch and a preparation method thereof.The side, making contact with the skin of an object, of the memantine external transdermal patch serves as the inner side, and the transdermal patch comprises a backing layer, a medicine carrying layer and an anti-sticking protection layer which are sequentially arranged from outside to inside; the medicine carrying layer comprises a medicament containing an active ingredient memantine free alkali, a sustained-release material wrapping the medicament and a high-molecular viscous material; wherein the content of the medicament is 3-30 wt% on the basis of the medicament carrying layer. The memantine free alkali is wrapped by the slow-release material, then the slow-release material is added into the high-molecular viscous material, the medicament is wrapped but the cohesive force is not reduced after the medicament is mixed with the high-molecular viscous material, and the adhesive force of the high-molecular viscous material is ensured. Meanwhile, the degradation speed of the medicine carrying layer of the transdermal patch can be controlled according to addition of different sustained-release materials, controlled release of the medicine is achieved, and the sustained-release effect is achieved.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical preparation, and in particular to a memantine transdermal patch for external use and a preparation method thereof. Background Art

[0002] Memantine hydrochloride is an N-methyl-D-aspartate (NMDA) receptor antagonist, primarily used to treat moderate to severe Alzheimer's disease (AD). Currently marketed dosage forms include tablets, capsules, and oral solutions, all of which are oral preparations. There is no information on the market for topical preparations. Currently marketed oral tablet dosage forms are mostly taken once or twice a day, and tablets have a gradient dosing pattern depending on the indication. This makes it difficult for Alzheimer's patients to take the drug, and it is difficult to control the daily medication schedule.

[0003] Transdermal drug delivery systems are a successful platform for sustained and controlled release. Currently, a variety of drugs have been developed and marketed, enabling once-daily or even multi-day dosing. Memantine hydrochloride can be formulated into a transdermal patch, allowing for a dosing cycle of one patch every seven days. Compared to conventional oral administration, this greatly facilitates dosing for patients, reduces medication frequency, addresses gastrointestinal discomfort and dysphagia in some patients, and mitigates potential toxic side effects from cyclical drug effects. Furthermore, transdermal drug delivery can maintain stable blood drug concentrations for longer periods, making it the preferred dosage form for elderly patients.

[0004] Related art discloses a memantine transdermal delivery system whose composition contains a hydrophilic solvent carrier, which reduces the lipid solubility of the API and reduces its skin permeability. Other related art methods include a memantine transdermal delivery system containing an organic acid component, which not only reduces the logP of the free base, thereby reducing the API's skin permeability, but also exhibits a certain degree of skin irritation. Furthermore, some methods utilize a multilayer composite material of an acrylate polymer and a biocompatible polymer, and the drug is present as a mixture of hydrochloride and sodium bicarbonate, making it impossible to quantify the proportions of the free base and hydrochloride components. Related art also discloses a long-acting memantine hydrochloride transdermal patch, in which the drug component accounts for a low proportion of 0.4% to 1.5%, resulting in oversized drug products and poor application compliance. Furthermore, some methods disclose the formation of white floccules when a pressure-sensitive adhesive with carboxyl end groups is mixed with memantine base, leading to uneven mixing. Finally, a transdermal patch containing memantine incorporates an organic acid to reduce drug volatilization and control drug crystallization. This patent contains a high proportion of pharmaceutical components. However, since memantine in situ base is a fat-soluble compound, mixing it with a fat-soluble acrylic pressure-sensitive adhesive reduces the cohesive force between the components, leading to a decrease in adhesion. Therefore, while traditional formulations increase the drug loading of transdermal delivery systems, the patch's retention is significantly reduced, resulting in a decrease in retention. To ensure drug loading, developers need to prepare larger patches, which results in inconvenience and a high allergy rate.

[0005] At the same time, in the preparation of memantine transdermal patches, in order to achieve the effect of sustained release of the drug, the existing technology requires the addition of a sustained release layer, resulting in the need to prepare a multi-layer film during the preparation process, which undoubtedly increases the cost and preparation process.

[0006] Therefore, how to provide a memantine transdermal delivery system and a preparation method thereof, which can ensure the adhesion of the patch while increasing the drug loading amount and reducing the patch size, and at the same time achieve a sustained-release effect without adding a sustained-release layer and shorten the preparation process, is a technical problem that technicians in this field urgently need to solve. Summary of the Invention

[0007] The present application aims to at least partially address one of the technical problems in the related art. To this end, the present application aims to provide a memantine transdermal patch for external use and a method for preparing the same, thereby overcoming the technical problem of the antagonism between drug loading and viscosity in the related art transdermal patches for external use, and also addressing the problem of conventional transdermal patches being too large and having a low drug delivery duration.

[0008] To achieve the above-mentioned objectives, according to a first aspect of the present application, a memantine transdermal patch for external use is provided, wherein the side contacting the subject's skin is the inner side, and the transdermal patch comprises, from the outer to the inner side, a backing layer, a drug-carrying layer, and an anti-adhesive protective layer; the drug-carrying layer comprises a drug containing the active ingredient memantine free base, a sustained-release material encapsulating the drug, and a polymer adhesive material; wherein the drug content is 3-30 wt % based on the drug-carrying layer.

[0009] In some embodiments, based on the drug-carrying layer, the content of the sustained-release material is 10-20 wt %; the content of the high molecular weight viscous material is 50-80 wt %.

[0010] In some embodiments, the drug-carrying layer further comprises a penetration enhancer, and the content of the penetration enhancer is 2-10 wt % based on the drug-carrying layer.

[0011] In some embodiments, the penetration enhancer is at least one of polysorbate 80, azone, oleic acid, menthol, or isopropyl myristate.

[0012] In some embodiments, the polymer adhesive material is selected from at least one of a water-soluble acrylic pressure-sensitive adhesive, a fat-soluble acrylic pressure-sensitive adhesive, and a silicone pressure-sensitive adhesive.

[0013] In some embodiments, the sustained-release material is selected from at least one of lactide-co-glycolide copolymer, polylactic acid, polycaprolactone, hypromellose, or ethyl cellulose.

[0014] In some embodiments, the backing layer is any one of polyester, polyethylene, polypropylene, polyvinyl acetate resin, and a copolymer of ethylene and vinyl acetate.

[0015] In some embodiments, the anti-stick protective layer is composed of a silicon-coated polyester film.

[0016] According to a second aspect of the present application, a method for preparing the memantine transdermal patch described in any of the above embodiments is proposed, comprising the following steps:

[0017] Dissolving the drug and the sustained-release material in an organic reagent to obtain a first mixed solution; adding a polymer viscous material to the first mixed solution to obtain a drug storage ointment;

[0018] The drug storage ointment is coated on the anti-sticking protective layer and solidified to form a fixed shape. After it is completely dried, a backing layer is attached to one side of the drug-carrying layer formed by the drug storage ointment and cut into shape.

[0019] In some embodiments, the organic solvent is selected from at least one of N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, ethyl acetate, ethyl benzoate, benzyl benzoate, and benzyl alcohol.

[0020] In some embodiments, the drying method of the drug storage ointment is stage drying, wherein the first stage is drying at 50-60° C. for 15-25 min; and the second stage is drying at 75-85° C. for 15-25 min.

[0021] Compared with the existing technology, this application has the following beneficial technical effects:

[0022] The present application ensures the adhesion of the patch while increasing the drug loading capacity and reducing the size of the memantine topical transdermal patch. At the same time, a single-layer preparation is used. Compared with the double-layer preparation method using the addition of a controlled-release membrane in the related art, the same sustained-release effect can be achieved while reducing the preparation process. Therefore, the present application ensures the drug loading capacity and adhesion of the transdermal patch, while ensuring the sustained-release effect and simplifying the preparation process.

[0023] In addition, the sustained-release material of the present application is biodegradable. After contacting with skin moisture, it can gradually degrade into lactic acid and hydroxybutyric acid. The degradation rate can be controlled according to different types of sustained-release materials to achieve controlled release of the drug and achieve a sustained-release effect.

[0024] Additional aspects and advantages of the present application will be given in part in the description below, and in part will become apparent from the description below, or will be learned through practice of the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The above and / or additional aspects and advantages of the present application will become apparent and easily understood from the following description of the embodiments in conjunction with the accompanying drawings, in which:

[0026] Figure 1 Schematic diagram of the structure of the memantine transdermal patch provided in this application;

[0027] Figure 2 is a flow chart of the method for preparing a memantine transdermal patch provided in the present application;

[0028] in Figure 1 Among them, 1. anti-sticking protective layer; 2. drug-carrying layer; 3. backing layer. DETAILED DESCRIPTION

[0029] The embodiments of the present application are described in detail below. Examples of the embodiments are shown in the accompanying drawings, wherein the same or similar reference numerals throughout represent the same or similar elements or elements having the same or similar functions. The embodiments described below with reference to the accompanying drawings are exemplary and are intended only to explain the present application and are not to be construed as limiting the present application. On the contrary, the embodiments of the present application include all variations, modifications, and equivalents that fall within the spirit and scope of the appended claims.

[0030] To achieve the above objectives, according to a first aspect of the present application, a memantine transdermal patch for external use is provided. The transdermal patch comprises, with the side contacting the subject's skin as the inner side, a backing layer 3, a drug-carrying layer 2, and an anti-adhesive protective layer 1, arranged in order from the outside to the inside. The drug-carrying layer 2 comprises a drug containing the active ingredient memantine free base, a sustained-release material encapsulating the drug, and a polymer adhesive material. The drug content is 3-30 wt % based on the drug-carrying layer 2.

[0031] Among them Figure 1 The memantine transdermal patch for external use in the present application has the side that contacts the subject's skin as the inner side, and the direction from outside to inside is as indicated in the figure. The memantine transdermal patch for external use comprises, from outside to inside, a backing layer 3, a drug-carrying layer 2, and an anti-adhesive protective layer 1; wherein the backing layer 3 is any one of polyester, polyethylene, polypropylene, polyvinyl acetate resin, and a copolymer of ethylene and vinyl acetate; preferably, the backing layer 3 is a polyester film; it is the outermost side that contacts the subject's skin, is used to protect the subject's skin, and has waterproof and antibacterial effects.

[0032] In this embodiment, the anti-adhesive protective layer 1 is composed of a silicone-coated polyester film. When the user needs to apply the memantine transdermal patch, the anti-adhesive protective layer 1 can be removed, and the drug-carrying layer 2 can be directly placed in contact with the skin. The drug-carrying layer 2 in this embodiment includes a drug containing the active ingredient, memantine free base, a sustained-release material encapsulating the drug, and a polymeric adhesive material. The polymeric adhesive material is selected from at least one of a water-soluble acrylic pressure-sensitive adhesive, a fat-soluble acrylic pressure-sensitive adhesive, or a silicone pressure-sensitive adhesive. The polymeric adhesive material is preferably a fat-soluble acrylic pressure-sensitive adhesive, with DURO-TAK387-2287 and DURO-TAK387-2510 pressure-sensitive adhesive being preferred.

[0033] In this embodiment, the sustained-release material is selected from at least one of poly(lactide-co-glycolide) (PLGA), polylactic acid, polycaprolactone, hypromellose, or ethyl cellulose; preferably, PLGA. Furthermore, in some embodiments, the sustained-release material preferably comprises PLGA having a molecular weight range of 1,000-100,000; or the sustained-release material preferably comprises PLGA having a molar ratio of lactide to glycolide of 25-50:50-75.

[0034] In this embodiment, the drug content in the drug-carrying layer 2 is 3-30 wt %, wherein the drug content is 3 wt %, 10 wt %, 15 wt %, 18 wt %, 20 wt %, 25 wt %, or 30 wt %, or any value within these ranges. Furthermore, the drug content in the drug-carrying layer is 10-20 wt %. Furthermore, the drug content in the drug-carrying layer is 15 wt %. It is known that after the traditional prescription increases the drug loading of the transdermal delivery system, the adhesion of the patch will be greatly reduced, resulting in a decrease in the adhesion force. In order to ensure the drug loading, the researchers need to prepare patches with larger areas, which makes it inconvenient to use and has a high allergy rate. Therefore, the present application takes into account the drug loading while ensuring the adhesion of the memantine topical transdermal patch. When the drug content is lower than 3wt%, the effect of the memantine topical transdermal patch with a small drug loading is limited; when the drug content is higher than 30wt%, its adhesion effect is poor when it is in a suitable size, such as a circular patch with a diameter of 6 cm, and the drug delivery duration is low.

[0035] In some embodiments, based on the drug-carrying layer 2, the sustained-release material is 10-20 wt%; the high molecular weight viscous material is 50-80 wt%.

[0036] The sustained-release material content in the drug-loading layer 2 is 10-20 wt %; the sustained-release material content is 10 wt %, 15 wt %, 18 wt % or 20 wt % or any value within the range. Furthermore, the sustained-release material content in the drug-loading layer is 10-20 wt %; further, the sustained-release material content in the drug-loading layer is 15 wt %.

[0037] The polymer viscous material content is 50-80 wt %, wherein the polymer viscous material content is 50 wt %, 67 wt %, 78 wt % or 80 wt % or any value within the range. Further, the polymer viscous material content in the drug-carrying layer is 50-70 wt %; further, the polymer viscous material content in the drug-carrying layer is 67 wt %.

[0038] In some embodiments, the drug-carrying layer 2 further comprises a penetration enhancer, and the penetration enhancer is 2-10 wt % based on the drug-carrying layer 2. Furthermore, the penetration enhancer content in the drug-carrying layer is 4-8 wt %; further, the penetration enhancer content in the drug-carrying layer is 5 wt %.

[0039] The drug-carrying layer 2 further comprises a penetration enhancer, which is at least one of polysorbate 80, azone, oleic acid, menthol, and isopropyl myristate. The penetration enhancer is present in an amount of 2-10 wt % based on the drug-carrying layer 2. The penetration enhancer content is 2 wt %, 5 wt %, 8 wt %, or 10 wt %, or any value within the range. Furthermore, the penetration enhancer is isopropyl myristate.

[0040] According to the second aspect of the present application, a method for preparing the memantine transdermal patch of any of the above embodiments is proposed, such as Figure 2 , including the following steps:

[0041] S1: dissolving a drug and a sustained-release material into an organic reagent to obtain a first mixed solution; adding a polymer viscous material to the first mixed solution to obtain a drug storage ointment;

[0042] S2: The drug storage ointment is coated on the anti-adhesive protective layer 1 and solidified. After it is completely dry, a backing layer 3 is attached to one side of the drug-carrying layer 2 formed by the drug storage ointment and cut into shape.

[0043] In S1, the drug and the sustained-release material in a set ratio are dissolved in an organic reagent, mixed, and thoroughly mixed and stirred at room temperature to obtain a first mixed solution, wherein the organic solvent is selected from one or a combination of N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, ethyl acetate, ethyl benzoate, benzyl benzoate, and benzyl alcohol, preferably ethyl acetate; a polymer viscous material is added to the first mixed solution to obtain a drug storage ointment, and thoroughly mixed and stirred at room temperature to obtain a drug storage ointment;

[0044] In some embodiments, the drug storage ointment also contains a penetration enhancer. In this case, the first mixed solution and the penetration enhancer are added to the high molecular weight viscous material, and the mixture is thoroughly mixed and stirred at room temperature to obtain the drug storage ointment.

[0045] In S2, the drug storage ointment is applied to the anti-adhesive protective layer 1 and cured using a staged drying method. The first stage is drying at 50-60°C for 15-25 minutes, followed by drying at 75-85°C for 15-25 minutes. After the drug storage ointment is completely dry, a backing layer 3 is attached to one side of the drug-carrying layer 2 formed by the drug storage ointment and cut into shapes, for example, into circular patches with a diameter of 6 cm.

[0046] The following is a specific example. It is well known in the art that the pressure-sensitive adhesive used during use is usually a wet adhesive with a certain acrylic pressure-sensitive adhesive solid content (for example, the solid content of DURO-TAK 387-2510 is 50.4%). The content of the acrylic pressure-sensitive adhesive in this application is calculated based on the acrylic pressure-sensitive adhesive solid content.

[0047] Example 1

[0048] A memantine transdermal patch for external use, the components of which are shown in Table 1:

[0049] Table 1 Composition of memantine transdermal patch for external use

[0050]

[0051] The preparation process is as follows: PLGA (sustained-release material) and memantine free base are added to ethyl acetate and stirred at room temperature to dissolve to obtain a first mixed solution. The first mixed solution and isopropyl myristate are added to DURO-TAK387-2510 (acrylate pressure-sensitive adhesive) and thoroughly mixed at room temperature to obtain a drug storage plaster. The resulting drug storage plaster is then coated onto a silicone-coated polyester film anti-adhesive layer and dried at 55°C for 20 minutes and then at 80°C for 20 minutes. After drying, the polyester film is applied as a backing layer over the drug storage plaster, and the resulting patch is cut into circular patches with a diameter of 6 cm.

[0052] Example 2

[0053] A memantine transdermal patch for external use, the components of which are shown in Table 2:

[0054] Table 2 Composition of memantine transdermal patch for external use

[0055]

[0056] The preparation process is as follows: PLGA and memantine free base are added to methanol and stirred at room temperature to dissolve to obtain a first mixed solution. This first mixed solution is then added to DURO-TAK 387-2510 acrylic pressure-sensitive adhesive and thoroughly mixed at room temperature to obtain a reservoir plaster. The resulting reservoir plaster is then coated onto a silicone-coated polyester film anti-adhesive layer and dried at 60°C for 20 minutes and 75°C for 20 minutes. After drying, a polyethylene film backing layer is applied to the reservoir plaster, and the resulting patch is cut into circular patches with a diameter of 6 cm.

[0057] Example 3

[0058] A memantine transdermal patch for external use, the components of which are shown in Table 3:

[0059] Table 3 Composition of memantine transdermal patch for external use

[0060] Drug-Loading Layer Prescription Information Mass ratio wt% Memantine 30 polylactic acid 10 Polysorbate 80 8 Acrylic pressure-sensitive adhesive 2287 (based on dry product) 52 Dimethylacetamide (removed during the process) appropriate amount

[0061] The preparation process is as follows: The sustained-release materials polylactic acid and memantine free base are added to dimethylacetamide and stirred at room temperature to dissolve to obtain a first mixed solution. The first mixed solution and polysorbate 80 are then added to the acrylic pressure-sensitive adhesive DURO-TAK387-2287 and thoroughly mixed at room temperature to obtain a drug storage plaster. The resulting drug storage plaster is then coated onto a silicone-coated polyester film anti-adhesive layer and dried at 50°C for 25 minutes and then at 75°C for 25 minutes. After drying, a polypropylene film backing layer is applied to the drug storage plaster, and the resulting patch is cut into circular patches with a diameter of 6 cm.

[0062] Example 4

[0063] A memantine transdermal patch for external use, the components of which are shown in Table 4:

[0064] Table 4 Composition of memantine transdermal patch for external use

[0065] Drug-Loading Layer Prescription Information Mass ratio wt% Memantine 5 Ethyl cellulose 18 Menthol 5 Acrylic pressure-sensitive adhesive 2287 (based on dry product) 72 N-Methylpyrrolidone appropriate amount

[0066] The preparation process is as follows: ethyl cellulose and memantine free base, a sustained-release material, are added to N-methylpyrrolidone and stirred at room temperature to dissolve to obtain a first mixed solution. This first mixed solution and menthol are then added to DURO-TAK387-2287, an acrylic pressure-sensitive adhesive, and thoroughly mixed and stirred at room temperature to obtain a reservoir plaster. The resulting reservoir plaster is then coated onto a release layer composed of a silicone-coated polyester film and dried at 58°C for 15 minutes and then at 85°C for 25 minutes. After drying, a vinyl film backing layer is applied to the reservoir plaster, and the resulting patch is cut into circular patches with a diameter of 8 cm.

[0067] Comparative Example 1

[0068] A memantine transdermal patch for external use, the components of which are shown in Table 5:

[0069] Table 5 Composition of memantine transdermal patch for external use

[0070]

[0071]

[0072] The preparation process is as follows: ethyl cellulose and memantine free base, a sustained-release material, are added to N-methylpyrrolidone and stirred at room temperature to dissolve to obtain a first mixed solution. This first mixed solution and menthol are then added to DURO-TAK387-2287, an acrylic pressure-sensitive adhesive, and thoroughly mixed and stirred at room temperature to obtain a reservoir plaster. The resulting reservoir plaster is then coated onto a release layer composed of a silicone-coated polyester film and dried at 58°C for 15 minutes and then at 85°C for 25 minutes. After drying, a vinyl film backing layer is applied to the reservoir plaster, and the resulting patch is cut into circular patches with a diameter of 6 cm.

[0073] Comparative Example 2

[0074] A memantine transdermal patch for external use, the components of which are shown in Table 6:

[0075] Table 6 Composition of memantine transdermal patch for external use

[0076] Drug-Loading Layer Prescription Information Mass ratio wt% Memantine 5 Ethyl cellulose 18 Menthol 5 Acrylic pressure-sensitive adhesive 2287 (based on dry product) 72 N-Methylpyrrolidone appropriate amount

[0077] The preparation process is as follows: ethyl cellulose and memantine free base, a sustained-release material, are added to N-methylpyrrolidone and stirred at room temperature to dissolve to obtain a first mixed solution. This first mixed solution and menthol are then added to DURO-TAK387-2287, an acrylic pressure-sensitive adhesive, and thoroughly mixed and stirred at room temperature to obtain a reservoir plaster. The resulting reservoir plaster is then coated onto a silicone-coated polyester film anti-adhesive layer and dried at 60°C for 50 minutes. After drying, a vinyl film backing layer is applied to the reservoir plaster, and the resulting patch is cut into circular patches with a diameter of 6 cm.

[0078] Comparative Example 3

[0079] A memantine transdermal patch for external use, the components of which are shown in Table 7:

[0080] Table 7 Composition of memantine external transdermal patch

[0081] Drug-Loading Layer Prescription Information Mass ratio wt% Memantine 30 Isopropyl myristate 3 Acrylic pressure-sensitive adhesive 2510 (based on dry product) 67 Ethyl acetate (removed during the process) appropriate amount

[0082] The preparation process is as follows: Memantine free base is added to ethyl acetate and stirred at room temperature to dissolve to obtain a first mixed solution. The first mixed solution and isopropyl myristate are added to DURO-TAK 387-2510 acrylic pressure-sensitive adhesive and thoroughly mixed at room temperature to obtain a reservoir plaster. The resulting reservoir plaster is coated onto a release layer composed of a silicone-coated polyester film and dried at 55°C for 20 minutes and then at 80°C for 20 minutes. After drying, a vinyl film backing layer is applied to the reservoir plaster, and the resulting patch is cut into circular patches with a diameter of 6 cm.

[0083] Comparative Example 4

[0084] A memantine transdermal patch for external use, the components of which are shown in Table 8:

[0085] Table 8 Composition of memantine transdermal patch for external use

[0086]

[0087] The preparation process is as follows: PLGA (sustained-release material) and memantine free base are added to ethyl acetate and stirred at room temperature to dissolve to obtain a first mixed solution. The first mixed solution and isopropyl myristate are added to DURO-TAK387-2510 (acrylate pressure-sensitive adhesive) and thoroughly mixed at room temperature to obtain a drug storage plaster. The resulting drug storage plaster is then coated onto a silicone-coated polyester film anti-adhesive layer and dried at 55°C for 20 minutes and then at 80°C for 20 minutes. After drying, a vinyl film backing layer is applied to the drug storage plaster, and the resulting patch is cut into circular patches with a diameter of 6 cm.

[0088] Experimental example

[0089] The performance test of the memantine topical transdermal patches obtained in Examples 1-4 and Comparative Examples 1-4 was performed in the following steps, wherein the release rate of the memantine topical transdermal patches was tested according to the fourth method of the dissolution and release determination method of the 2020 edition of the Chinese Pharmacopoeia General Chapter 0931, wherein the medium used was 900 ml of a pH 7.4 medium, the rotation speed was 50 rpm, and the medium temperature was 32 ° C.

[0090] The adhesion of memantine transdermal patches was tested according to the second method of the Adhesion Force Determination Method in General Chapter 0952 of the 2020 edition of the Chinese Pharmacopoeia.

[0091] The properties of the samples of memantine transdermal patch were visually inspected.

[0092] The skin permeability of the memantine transdermal patch was determined using a Franz diffusion cell with a medium of pH 7.4, PBS buffer + 2% ethanol, a temperature of 32°C, a volume of 10 ml, and a rotation speed of 600 rpm; the skin was ex vivo skin of a 2-month-old Bama miniature pig with a skin thickness of about 1 mm.

[0093] The performance results of the memantine transdermal patches obtained in Examples 1-4 and Comparative Examples 1-4 are shown in Table 9.

[0094] Table 9 Performance test results of memantine external transdermal patches of Examples 1-4 and Comparative Examples 1-4

[0095]

[0096]

[0097] Compared to Example 1, Example 2 does not contain a permeation enhancer. According to the skin permeation rate data in Table 9, its skin permeation rate is lower than that of Example 1, at 44%. In Comparative Example 1, the amount of polymer material used is too low. Compared with Example 4, according to the adhesion data in Table 9, it can be seen that reducing the amount of polymer material used leads to a decrease in the adhesion durability of the memantine transdermal patch. In Comparative Example 3, no sustained-release material is added, resulting in decreased adhesion and accelerated drug release. The adhesion data in Comparative Example 3 decreased because the memantine free base in the drug was not coated with a sustained-release material. The memantine free base was in direct contact with the polymer adhesive material over a large area, destroying the overall structure of the polymer adhesive material, reducing cohesion, and resulting in decreased adhesion. However, the use of a sustained-release material to coat the memantine free base in the embodiment prevents the drug from directly contacting the polymer adhesive material over a large area, thereby allowing the polymer adhesive material to play a greater role and maintaining the adhesion durability of the memantine transdermal patch.

[0098] At the same time, the choice of sustained-release material also affects the present application. For example, compared with Example 1, the molecular weight of the sustained-release material in Comparative Example 4 is larger. The molar percentage of lactide and glycolide in PLGA is 15:85, and when the molecular weight is 150,000, the drug release rate of the patch is too low to meet clinical needs.

[0099] Finally, in Comparative Example 2, only one drying step at 60° C. for 50 min was used, in which the organic reagent was not completely volatilized. The product had a strong pungent odor and a soft texture, which did not meet the requirements for patch properties. Therefore, no other tests were performed.

[0100] It should be noted that, in the description of this application, the terms "first", "second", etc. are used for descriptive purposes only and should not be understood as indicating or implying relative importance. In addition, in the description of this application, unless otherwise specified, the meaning of "plurality" is two or more.

[0101] Any process or method description in a flowchart or otherwise described herein may be understood to represent a module, segment or portion of code comprising one or more executable instructions for implementing the steps of a specific logical function or process, and the scope of the preferred embodiments of the present application includes alternative implementations in which functions may be performed out of the order shown or discussed, including performing functions in a substantially simultaneous manner or in the reverse order depending on the functions involved, which should be understood by those skilled in the art to which the embodiments of the present application belong.

[0102] Throughout this specification, reference to terms such as "one embodiment," "some embodiments," "examples," "specific examples," or "some examples" means that a specific feature, structure, material, or characteristic described in conjunction with that embodiment or example is included in at least one embodiment or example of the present application. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

[0103] Although the embodiments of the present application have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations on the present application. Ordinary technicians in this field can change, modify, replace and modify the above embodiments within the scope of the present application.

Claims

1. A memantine transdermal patch for external use, characterized in that The transdermal patch comprises, with the side contacting the subject's skin as the inner side, a backing layer, a drug-carrying layer, and an anti-adhesive protective layer arranged in order from the outside to the inside; the drug-carrying layer comprises a drug containing the active ingredient memantine free base, a sustained-release material encapsulating the drug, and a polymer adhesive material; wherein the drug content is 3-30 wt% based on the drug-carrying layer.

2. The memantine transdermal patch according to claim 1, wherein Based on the drug-carrying layer, the content of the sustained-release material is 10-20 wt %, and the content of the high-molecular viscosity material is 50-80 wt %.

3. The memantine transdermal patch for external use according to claim 1 or 2, wherein The drug-carrying layer further comprises a penetration enhancer. Based on the drug-carrying layer, the content of the penetration enhancer is 2-10 wt %.

4. The memantine transdermal patch for external use according to claim 3, wherein The penetration enhancer is at least one of polysorbate 80, azone, oleic acid, menthol or isopropyl myristate.

5. The memantine transdermal patch for external use according to claim 1, wherein The polymer adhesive material is selected from at least one of water-soluble acrylic pressure-sensitive adhesive, fat-soluble acrylic pressure-sensitive adhesive or silicone pressure-sensitive adhesive.

6. The memantine transdermal patch for external use according to claim 1, wherein The sustained-release material is selected from at least one of lactide-co-glycolide copolymer, polylactic acid, polycaprolactone, hydroxypropyl methylcellulose or ethyl cellulose.

7. The memantine transdermal patch for external use according to claim 1, wherein The backing layer is any one of polyester, polyethylene, polypropylene, polyvinyl acetate resin, and a copolymer of ethylene and vinyl acetate.

8. A method for preparing the memantine transdermal patch as claimed in any one of claims 1 to 7, characterized in that: The following steps are involved: Dissolving the drug and the sustained-release material in an organic reagent to obtain a first mixed solution; adding a polymer viscous material to the first mixed solution to obtain a drug storage ointment; The drug storage ointment is coated on the anti-sticking protective layer and solidified to form a fixed shape. After it is completely dried, a backing layer is attached to one side of the drug-carrying layer formed by the drug storage ointment and cut into shape.

9. The method according to claim 8, characterized in that The organic solvent is selected from at least one of N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, ethyl acetate, ethyl benzoate, benzyl benzoate and benzyl alcohol.

10. The method according to claim 8, characterized in that The drying method of the drug storage ointment is stage drying, including: drying at 50-60° C. for 15-25 minutes in the first stage and drying at 75-85° C. for 15-25 minutes in the second stage.

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