Galanthamine hydrobromide transdermal patch containing penetration enhancer composition and preparation method of galanthamine hydrobromide transdermal patch

Abstract

The invention discloses a galanthamine hydrobromide transdermal patch containing a penetration enhancer composition and a preparation method of the galanthamine hydrobromide transdermal patch, and belongs to the technical field of pharmaceutical preparations. The formula of the galanthamine hydrobromide transdermal patch comprises galanthamine hydrobromide, a penetration enhancer combination, a pressure-sensitive adhesive matrix, an antioxidant and a solvent, through the synergistic effect of the specific penetration enhancer combination, the skin cuticle barrier is effectively broken through, the transdermal efficiency of the galanthamine hydrobromide is remarkably improved, and the transdermal patch has a good application prospect. Meanwhile, due to the dosage form of the transdermal patch, the first-pass effect of the liver and the adverse reaction of the gastrointestinal tract can be avoided, the compliance of a patient is improved, and the transdermal patch is suitable for treating nervous system diseases such as mild to moderate Alzheimer's disease.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a transdermal patch of galanthamine hydrobromide containing a penetration enhancer combination and a preparation method thereof. BACKGROUND

[0002] Galanthamine hydrobromide, as a reversible cholinesterase inhibitor, plays an important role in the treatment of nervous system diseases, and is particularly suitable for improving memory impairment in patients with benign memory impairment, dementia and brain organic lesion, and has a therapeutic effect on myasthenia gravis and post-polio syndrome. Its mechanism of action is to improve nerve-muscle junction transmission and central nervous system synaptic function by inhibiting cholinesterase activity, and it has become one of the first-line drugs for mild to moderate Alzheimer's disease.

[0003] However, the existing administration mode has significant limitations. Oral preparations (such as tablets) need to be administered frequently (the initial dose is 5 mg at a time, 4 times a day), and can easily cause adverse reactions in the gastrointestinal tract (such as nausea, abdominal pain, loss of appetite, etc.), and the bioavailability is greatly affected by the liver first-pass effect. Although injection can quickly take effect, it needs to be operated by professional personnel, and long-term use can cause pain and inconvenience to patients, especially for patients with senile dementia who need long-term medication. In addition, whether oral or injection administration, it is difficult to maintain a stable blood drug concentration, which may lead to fluctuation of efficacy or increased risk of adverse reactions.

[0004] As a new type of drug administration method, transdermal drug delivery system has the advantages of avoiding liver first-pass effect, reducing gastrointestinal irritation, stable blood drug concentration and high patient compliance, and has been successfully applied in fentanyl, ketoprofen and other drugs. However, the transdermal absorption of galanthamine hydrobromide faces inherent challenges: its molecular structure has the characteristics of four-ring alkaloids, the balance between liposolubility and water solubility is not good, and the barrier effect of the stratum corneum makes its transdermal rate low, making it difficult to reach the effective concentration required for treatment.

[0005] Chinese Patent No. CN101455651A discloses a skin patch for improving the symptoms of dementia, delusion and myasthenia caused by cholinergic deficiency, and the drug is galanthamine or its hydrobromide salt, and the transdermal penetration enhancer is azone. In the prior art, the penetration enhancement scheme for transdermal patches mostly uses a single penetration enhancer (such as azone, polyethylene glycol, etc.), which can improve the permeability of the drug to a certain extent, but has limitations: azone has limited penetration enhancement effect on hydrophilic drugs, and high concentrations of polyethylene glycol are needed when used alone, which may cause skin irritation.

[0006] With the increasing incidence of Alzheimer's disease worldwide, there is an urgent need for a long-acting, safe drug delivery system for galantamine hydrobromide in clinical practice. The development of a transdermal patch containing a combination of high-efficiency penetration enhancers can not only solve the problems of adverse reactions and compliance of existing dosage forms, but also break through the technical bottleneck of single penetration enhancer, which is of great significance to improve treatment efficacy and improve the quality of life of patients. SUMMARY

[0007] To overcome the low transdermal absorption efficiency of galantamine hydrobromide, the limited effect of single penetration enhancer and the obvious adverse reactions of existing dosage forms in the prior art, the present application provides a transdermal patch of galantamine hydrobromide containing a combination of penetration enhancers and a preparation method thereof, aiming to achieve efficient and stable transdermal delivery of drugs, improve treatment efficacy and patient compliance by optimizing the formula and process.

[0008] The transdermal patch of galantamine hydrobromide of the present application comprises, by weight percentage: Active ingredient: 1.0-4.0% galantamine hydrobromide, as the core component of treatment, which exerts a neuromodulatory effect by inhibiting cholinesterase activity; Penetration enhancer combination: composed of azone, 2,6-nonadienol and L-lysine, wherein azone accounts for 2.5-3.5%, 2,6-nonadienol accounts for 1.0-2.5%, and L-lysine accounts for 1.0-1.5%, the three components synergistically enhance the transdermal efficiency of the drug; Pressure-sensitive adhesive matrix: 60.0-70.0% solvent-type acrylate, responsible for fixing the drug and excipients and adhering to the skin, while controlling the release rate of the drug; Antioxidant: 0.08-0.12%, selected from at least one of 2,6-di-tert-butyl-p-cresol, vitamin E and butylated hydroxyanisole, used to prevent oxidation and deterioration of the drug and excipients, prolonging the stability of the preparation; Solvent: ethanol-ethyl acetate mixture (1:1 by volume), supplemented to 100%, as a dispersion medium to promote the dissolution and mixing of the components.

[0009] The present application also provides a preparation method of the above-mentioned transdermal patch, comprising the following steps: (1) Preparation of matrix glue solution: add an appropriate amount of ethanol-ethyl acetate mixture to solvent-type acrylate pressure-sensitive adhesive, stir and disperse, then add antioxidant, continue to stir until completely dissolved, to obtain a uniform matrix glue solution; (2) Preparation of drug-penetration enhancer solution: add azone, 2,6-nonadienol and L-lysine to ethanol-ethyl acetate mixture, stir until dissolved, then refrigerate at 2-8℃ for 1-3 hours; add galantamine hydrobromide, ultrasonically treat to dissolve, filter through a 0.45μm microporous filter to remove bacteria, to obtain a clear drug-penetration enhancer solution; (3) Preparation of the glue-drug mixture: mix the matrix glue solution with the drug-penetration enhancer solution under vacuum (vacuum degree: -0.07 to -0.09 MPa), stir until uniform, vacuum degas for 25-35 minutes to remove bubbles, and obtain a uniform glue-drug mixture; (4) Coating and composite molding: coat the glue-drug mixture on the backing material (e.g., polyester, non-woven fabric, or aluminum-plastic composite film) at a thickness of 0.12-0.18 mm, dry at 35-45°C for 15-25 minutes to remove the solvent, and then composite with the protective layer (e.g., polytetrafluoroethylene, polyethylene, or silicone oil paper) to obtain the galantamine hydrobromide transdermal patch.

[0010] Galantamine hydrobromide has poor balance between liposolubility and water solubility due to its molecular structure (tetracyclic alkaloid), low transdermal absorption efficiency, and difficulty in meeting the treatment requirements with a single penetration enhancer. The present application uses the combination of azone, 2,6-nonadienol, and L-lysine to break through the stratum corneum barrier through multi-mechanism synergy, significantly improving the transdermal efficiency, and the specific effects are as follows: Azone (lauryl azone) is a classic liposoluble penetration enhancer that can insert into the lipid bilayer of the stratum corneum, disrupt the order of lipid arrangement, reduce the adhesion between lipids, make the structure of the stratum corneum loose, and form a "lipophilic channel". It provides a basic channel for the penetration of subsequent drugs and other penetration enhancers, especially enhances the skin penetration ability of liposoluble components (such as 2,6-nonadienol), and creates space for the transmembrane diffusion of water-soluble drugs (galantamine hydrobromide). 2,6-Nonadienol: as an unsaturated alcohol compound, it has a certain liposolubility and can interact with keratin and lipid components in the stratum corneum, reducing the interfacial tension between the drug and the skin and increasing the solubility of galantamine hydrobromide in the stratum corneum. It is complementary to azone, reduces the retention of the drug on the skin surface, and accelerates its transport to the dermis. L-lysine is a polar amino acid with hydrophilic groups (amino and carboxyl groups), which can make up for the deficiency of azone in promoting the penetration of water-soluble drugs, solve the problem of imbalance between the water solubility and the liposolubility of galantamine hydrobromide, and enable the drug to diffuse efficiently in both the lipophilic channel (mediated by azone) and the hydrophilic channel (mediated by L-lysine). Azone, 2,6-nonadienol, and L-lysine synergize to form a synergistic penetration network, significantly improving the transdermal efficiency and providing key technical support for the clinical application of galantamine hydrobromide transdermal patches.

[0011] Compared with the prior art, the technical effect of the present application is as follows: (1) Significant penetration effect: the present application uses the synergy of azone, 2,6-nonadienol, and L-lysine to solve the problem of imbalance between the liposolubility and the water solubility of galantamine hydrobromide, and the three form a "lipophilic-hydrophilic balanced channel" to significantly improve the transdermal efficiency.

[0012] (2) Good safety and compliance: transdermal administration avoids liver first-pass effect and gastrointestinal irritation, reduces adverse reactions such as nausea and abdominal pain; the patch can stably release drugs, maintain stable blood drug concentration, reduce the risk of efficacy fluctuations, and significantly improve the compliance of patients with long-term medication needs such as Alzheimer's disease. BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 Cumulative permeation amount of galanthamine hydrobromide transdermal patch of Examples 1-3 and Comparative Examples 1-6. DETAILED DESCRIPTION

[0014] In order to make the purpose, technical solutions of the present application more clear, the following embodiments are combined to further illustrate the present application, but the protection scope of the present application is not limited to these embodiments, and the embodiments are only used to explain the present application. Those skilled in the art should understand that any changes or equivalent replacements without departing from the concept of the present application are included in the protection scope of the present application.

[0015] Example 1 galanthamine hydrobromide transdermal patch Formula: Preparation method: (1) Preparation of matrix glue solution: take 65.0% of the total system of solvent type acrylic ester pressure sensitive adhesive, add an appropriate amount of ethanol-ethyl acetate mixed solution with a volume ratio of 1:1, stir for 30 minutes until uniformly dispersed, then add 0.04% of 2,6-di-tert-butyl-p-cresol, 0.03% of vitamin E and 0.03% of butylated hydroxyanisole of the total system, continue to stir for 20 minutes until completely dissolved and mixed, to obtain the matrix glue solution.

[0016] (2) Preparation of drug-penetration enhancer solution: in the ethanol-ethyl acetate mixed solution with a volume ratio of 1:1, add 3.0% of azone, 1.5% of 2,6-nonadienol and 1.2% of L-lysine of the total system, stir for 15 minutes until completely dissolved, and store at 2~8℃ for 2 hours. Add 2% galanthamine hydrobromide, ultrasonic treatment for 10 minutes to make it fully dissolved, then microfiltration sterilization through 0.45μm microporous filter membrane to obtain the drug-penetration enhancer solution.

[0017] (3) Preparation of glue-drug mixture: under the condition of vacuum degree of-0.08MPa, mix the matrix glue solution obtained in step (1) with the drug-penetration enhancer solution obtained in step (2), stir for 15 minutes until uniform, then degas for 30 minutes under the same vacuum degree to remove bubbles, to obtain the glue-drug mixture.

[0018] (4) Coating and composite molding: the glue-medicine mixture is coated on the polyester backing material with a thickness of 0.15 mm, dried at 40°C for 20 minutes, and then compounded with a polytetrafluoroethylene protective layer to form a 1.0 mg / cm2 galanthamine hydrobromide transdermal patch.

[0019] Example 2 Galanthamine hydrobromide transdermal patch Formulation: Preparation method: (1) Preparation of base glue solution: take 60.0% of the total system solvent type acrylic pressure sensitive adhesive, add an appropriate amount of volume ratio 1:1 ethanol-ethyl acetate mixed solution, stir for 25 minutes until uniformly dispersed, then add 0.05% of the total system 2,6-di-tert-butyl-p-cresol and 0.03% of butylated hydroxyanisole, continue to stir for 15 minutes until completely dissolved and mixed to obtain the base glue solution.

[0020] (2) Preparation of drug-penetration enhancer solution: add 2.5% of the total system azone, 1.0% of 2,6-nonadienol, and 1.0% of L-lysine to the volume ratio 1:1 ethanol-ethyl acetate mixed solution, stir for 12 minutes until completely dissolved, and store in a 2-8°C environment for 1 hour. Add 1% galanthamine hydrobromide, and ultrasonically treat for 8 minutes to fully dissolve. After sterilization by 0.45 μm microporous filter membrane, the drug-penetration enhancer solution is obtained.

[0021] (3) Preparation of glue-medicine mixture: mix the base glue solution and the drug-penetration enhancer solution in a vacuum environment with a vacuum degree of -0.07 MPa, stir for 12 minutes until uniform, then degas for 25 minutes under the same vacuum degree to remove bubbles in the mixture, and obtain the glue-medicine mixture.

[0022] (4) Coating and composite molding: uniformly coat the glue-medicine mixture on the non-woven backing material with a coating thickness of 0.12 mm, dry at 35°C for 25 minutes, then compound with a polyethylene protective layer to complete the molding of the 0.5 mg / cm2 galanthamine hydrobromide transdermal patch.

[0023] Example 3 Galanthamine hydrobromide transdermal patch Formulation: Preparation method: (1) Preparation of base glue solution: take 70.0% of the total system solvent type acrylic pressure sensitive adhesive, add an appropriate amount of volume ratio 1:1 ethanol-ethyl acetate mixed solution, stir for 35 minutes until uniformly dispersed, then add 0.12% of the total system 2,6-di-tert-butyl-p-cresol, continue to stir for 25 minutes until completely dissolved and mixed to obtain the base glue solution.

[0024] (2) Drug-penetration enhancer solution preparation: In a mixture of ethanol-ethyl acetate with a volume ratio of 1:1, add 3.5% of azone, 2.5% of 2,6-nonadienol, and 1.5% of L-lysine in the total system, stir for 18 minutes until dissolved, and store in a 2-8°C environment for 3 hours. Then add 4% of the added galantamine hydrobromide, and ultrasonically treat for 12 minutes to fully dissolve. Microfiltration through a 0.45 μm microporous filter to remove bacteria, to obtain a drug-penetration enhancer solution.

[0025] (3) Drug-gel mixture preparation: Mix the base gel solution with the drug-penetration enhancer solution under a vacuum of -0.09 MPa, stir for 18 minutes until uniform, and degas for 35 minutes under the same vacuum to remove air bubbles, to obtain a drug-gel mixture.

[0026] (4) Coating and composite molding: Coat the drug-gel mixture on an aluminum-plastic composite backing material at a thickness of 0.18 mm, dry at 45°C for 15 minutes, and then composite with a silicone oil paper protective layer, to produce a galantamine hydrobromide transdermal patch of 2.0 mg / cm².

[0027] Comparative Example 1 Galantamine hydrobromide transdermal patch Formulation: Preparation method: (1) Base gel solution preparation: Take 65.0% of a solvent-based acrylate pressure-sensitive adhesive in the total system, and add an appropriate amount of a mixture of ethanol-ethyl acetate with a volume ratio of 1:1, stir for 30 minutes until uniformly dispersed, then add 0.04% of 2,6-di-tert-butyl-p-cresol, 0.03% of vitamin E, and 0.03% of butylated hydroxyanisole in the total system, continue to stir for 20 minutes until completely dissolved and mixed, to obtain a base gel solution.

[0028] (2) Drug-penetration enhancer solution preparation: In a mixture of ethanol-ethyl acetate with a volume ratio of 1:1, add 3.0% of azone and 1.2% of L-lysine in the total system, stir for 15 minutes until completely dissolved, and store in a 2-8°C environment for 2 hours. Then add 2.0% of galantamine hydrobromide, ultrasonically treat for 10 minutes to fully dissolve, and microfiltration through a 0.45 μm microporous filter to remove bacteria, to obtain a drug-penetration enhancer solution.

[0029] (3) Drug-gel mixture preparation: Mix the base gel solution obtained in step (1) with the drug-penetration enhancer solution obtained in step (2) under a vacuum of -0.08 MPa, stir for 15 minutes until uniform, then degas for 30 minutes under the same vacuum to remove air bubbles, to obtain a drug-gel mixture.

[0030] (4) Coating and composite molding: the glue-medicine mixture was coated on the polyester backing material according to the thickness of 0.15 mm, dried at 40°C for 20 minutes, and then compounded with a polytetrafluoroethylene protective layer to finally form a 1.0 mg / cm2 galantamine hydrobromide transdermal patch.

[0031] Comparative Example 2 Galantamine Hydrobromide Transdermal Patch Formulation: Preparation method: (1) Preparation of base glue solution: 65.0% of the total system solvent type acrylate pressure sensitive adhesive was taken, and an appropriate amount of ethanol-ethyl acetate mixture with a volume ratio of 1:1 was added, stirred for 30 minutes until uniformly dispersed, then 0.04% of 2,6-di-tert-butyl-p-cresol, 0.03% of vitamin E and 0.03% of butylated hydroxyanisole of the total system were added, and the stirring was continued for 20 minutes until completely dissolved and mixed, to obtain the base glue solution.

[0032] (2) Preparation of drug-penetration enhancer solution: in the ethanol-ethyl acetate mixture with a volume ratio of 1:1, 3.0% of azone and 1.5% of 2,6-nonadienol of the total system were added, stirred for 15 minutes until completely dissolved, and stored at 2~8°C for 2 hours. 2.0% of galantamine hydrobromide was added, and ultrasonic treatment was performed for 10 minutes to fully dissolve it, and then microfiltration was performed through a 0.45 μm microporous filter to remove bacteria, to obtain the drug-penetration enhancer solution.

[0033] (3) Preparation of glue-medicine mixture: the base glue solution obtained in step (1) and the drug-penetration enhancer solution obtained in step (2) were mixed under the condition of vacuum degree of-0.08 MPa, stirred for 15 minutes until uniform, and then degassed for 30 minutes under the same vacuum degree to remove bubbles, to obtain the glue-medicine mixture.

[0034] (4) Coating and composite molding: the glue-medicine mixture was coated on the polyester backing material according to the thickness of 0.15 mm, dried at 40°C for 20 minutes, and then compounded with a polytetrafluoroethylene protective layer to finally form a 1.0 mg / cm2 galantamine hydrobromide transdermal patch.

[0035] Comparative Example 3 Galantamine Hydrobromide Transdermal Patch Formulation: Preparation method: (1) Preparation of matrix glue solution: Take 65.0% of the total system solvent type acrylate pressure sensitive adhesive, add an appropriate amount of volume ratio of 1:1 ethanol-ethyl acetate mixed solution, stir for 30 minutes to uniformly disperse, then add 0.04% of the total system 2,6-di-tert-butyl-p-cresol, 0.03% of vitamin E and 0.03% of butylated hydroxyanisole, continue to stir for 20 minutes to completely dissolve and mix, obtain the matrix glue solution.

[0036] (2) Preparation of drug-penetration enhancer solution: In the volume ratio of 1:1 ethanol-ethyl acetate mixed solution, add 3.0% of the total system azone, stir for 15 minutes to completely dissolve, and store in a 2~8℃ environment for 2 hours. Add 2.0% of hydrobromide galantamine, ultrasonic treatment for 10 minutes to fully dissolve, then microfiltration through 0.45μm microporous filter membrane to remove bacteria, obtain the drug-penetration enhancer solution.

[0037] (3) Preparation of glue-drug mixture: In the state of vacuum degree of-0.08MPa, mix the matrix glue solution obtained in step (1) with the drug-penetration enhancer solution obtained in step (2), stir for 15 minutes to be uniform, then degas for 30 minutes under the same vacuum degree to remove bubbles, obtain the glue-drug mixture.

[0038] (4) Coating and composite molding: The glue-drug mixture is coated on the polyester backing material with a thickness of 0.15mm, dried at 40℃ for 20 minutes, then compounded with polytetrafluoroethylene protective layer, finally molded into 1.0mg / cm² hydrobromide galantamine transdermal patch.

[0039] Comparative Example 4 Hydrobromide galantamine transdermal patch Formulation: Preparation method: (1) Preparation of matrix glue solution: Take 65.0% of the total system solvent type acrylate pressure sensitive adhesive, add an appropriate amount of volume ratio of 1:1 ethanol-ethyl acetate mixed solution, stir for 30 minutes to uniformly disperse, then add 0.04% of the total system 2,6-di-tert-butyl-p-cresol, 0.03% of vitamin E and 0.03% of butylated hydroxyanisole, continue to stir for 20 minutes to completely dissolve and mix, obtain the matrix glue solution.

[0040] (2) Preparation of drug-penetration enhancer solution: In the volume ratio of 1:1 ethanol-ethyl acetate mixed solution, add 3.0% of the total system azone, 1.5% of propylene glycol and 1.2% of L-lysine, stir for 15 minutes to completely dissolve, and store in a 2~8℃ environment for 2 hours. Add 2.0% of hydrobromide galantamine, ultrasonic treatment for 10 minutes to fully dissolve, then microfiltration through 0.45μm microporous filter membrane to remove bacteria, obtain the drug-penetration enhancer solution.

[0041] (3) Preparation of the drug-adhesive mixture: The base adhesive solution obtained in step (1) was mixed with the drug-penetration enhancer solution obtained in step (2) under a vacuum of -0.08 MPa, and stirred for 15 minutes until uniform. Then, the mixture was degassed for 30 minutes under the same vacuum to remove air bubbles, thereby obtaining the drug-adhesive mixture.

[0042] (4) Coating and composite molding: The drug-adhesive mixture was coated on the polyester backing material to a thickness of 0.15 mm, and dried at 40°C for 20 minutes. Then, the mixture was subjected to composite molding with a polytetrafluoroethylene protective layer, thereby finally molding a 1.0 mg / cm2 galantamine hydrobromide transdermal patch.

[0043] Comparative Example 5 Galantamine hydrobromide transdermal patch Formulation: Preparation method: (1) Preparation of the base adhesive solution: 65.0% of the total system of solvent-based acrylate pressure-sensitive adhesive was taken, and an appropriate amount of a mixture of ethanol and ethyl acetate (volume ratio of 1:1) was added thereto. After stirring for 30 minutes until uniform dispersion, 0.04% of 2,6-di-tert-butyl-p-cresol, 0.03% of vitamin E, and 0.03% of butylated hydroxyanisole of the total system were added, and stirring was continued for 20 minutes until complete dissolution and mixing. Thus, the base adhesive solution was obtained.

[0044] (2) Preparation of the drug-penetration enhancer solution: 5.0% of aminoxone, 0.5% of 2,6-nonadienol, and 0.5% of L-lysine of the total system were added to a mixture of ethanol and ethyl acetate (volume ratio of 1:1), and stirred for 15 minutes until complete dissolution. The mixture was then refrigerated at 2-8°C for 2 hours. 2.0% of galantamine hydrobromide was added, and ultrasonically treated for 10 minutes to completely dissolve the same. The resulting solution was microfiltered through a 0.45 μm pore size filter to remove bacteria, thereby obtaining the drug-penetration enhancer solution.

[0045] (3) Preparation of the drug-adhesive mixture: The base adhesive solution obtained in step (1) was mixed with the drug-penetration enhancer solution obtained in step (2) under a vacuum of -0.08 MPa, and stirred for 15 minutes until uniform. Then, the mixture was degassed for 30 minutes under the same vacuum to remove air bubbles, thereby obtaining the drug-adhesive mixture.

[0046] (4) Coating and composite molding: The drug-adhesive mixture was coated on the polyester backing material to a thickness of 0.15 mm, and dried at 40°C for 20 minutes. Then, the mixture was subjected to composite molding with a polytetrafluoroethylene protective layer, thereby finally molding a 1.0 mg / cm2 galantamine hydrobromide transdermal patch.

[0047] Comparative Example 6 Galantamine hydrobromide transdermal patch Formulation: Preparation method: (1) Preparation of matrix glue solution: Take 65.0% of the total system of solvent type acrylate pressure sensitive adhesive, add appropriate amount of volume ratio of 1:1 of ethanol-ethyl acetate mixed solution, stir for 30 minutes to uniformly disperse, then add 0.04% of 2,6-di-tert-butyl-p-cresol, 0.03% of vitamin E and 0.03% of butylated hydroxyanisole of the total system, continue to stir for 20 minutes to completely dissolve and mix, to obtain the matrix glue solution.

[0048] (2) Preparation of drug-penetration enhancer solution: In the volume ratio of 1:1 of ethanol-ethyl acetate mixed solution, add 3.0% of azone, 1.5% of 2,6-nonadienol and 1.2% of L-lysine of the total system, stir for 15 minutes to completely dissolve, add 2.0% of galantamine hydrobromide, ultrasonic treatment for 10 minutes to fully dissolve, then microfiltration through 0.45 μm microporous filter membrane to remove bacteria, to obtain the drug-penetration enhancer solution.

[0049] (3) Preparation of glue-drug mixture: Under the condition of vacuum degree of-0.08 MPa, mix the matrix glue solution obtained in step (1) with the drug-penetration enhancer solution obtained in step (2), stir for 15 minutes to be uniform, then degas for 30 minutes under the same vacuum degree to remove bubbles, to obtain the glue-drug mixture.

[0050] (4) Coating and composite molding: coat the glue-drug mixture on the polyester backing material according to the thickness of 0.15 mm, dry at 40℃ for 20 minutes, then composite with polytetrafluoroethylene protective layer, finally mold into 1.0 mg / cm² galantamine hydrobromide transdermal patch.

[0051] Galantamine hydrobromide transdermal patch penetration experiment Experimental materials and instruments Test sample: galantamine hydrobromide transdermal patches prepared in examples 1-3 and comparative examples 1-6 (the specification is unified to 1.0 mg / cm², if the specification is different, it is converted according to the area).

[0052] Animal skin: healthy male SD rats (body weight 250-300 g) were selected, the abdominal skin was peeled off after being sacrificed, the subcutaneous fat and connective tissue were removed, and the skin was washed clean with normal saline and stored at-20℃.

[0053] Receiving medium: pH 7.4 phosphate buffer (PBS) containing 20% ethanol.

[0054] Instruments: Franz diffusion cell (effective diffusion area 1.77 cm², receiving cell volume 5 mL), constant temperature water bath, magnetic stirrer, high performance liquid chromatograph.

[0055] Experimental method Skin pretreatment: After thawing, the rat skin was soaked in normal saline for 10 minutes, and the skin integrity was checked (no breakage, no bubbles). The skin was fixed between the donor chamber and the receiver chamber of the Franz diffusion cell, with the stratum corneum facing the donor chamber and the dermis facing the receiver chamber, ensuring that the skin was tightly attached to the diffusion cell without leakage.

[0056] Preparation of the receiver cell: The receiver medium was injected into the receiver chamber and preheated to 32°C to exclude bubbles. The constant temperature water bath circulation system was connected, and the magnetic stirring was started.

[0057] Test sample loading: Each patch (area 1.77 cm²) was removed from the protective layer and attached to the surface of the skin stratum corneum. The donor chamber was sealed, and the timer was started.

[0058] Sample collection: At 1, 2, 4, 6, 8, 12, and 24 hours, 1 mL of the receiver solution was taken each time (while adding an equal amount of fresh receiver medium at 32°C to maintain a constant volume). The sample was filtered through a 0.45 μm filter membrane, and the concentration of galantamine hydrobromide was determined by HPLC.

[0059] Evaluation index Cumulative permeation amount (Q, μg / cm²): The cumulative permeation amount of the drug at each time point was calculated according to the formula: Q = (C t ×V + ΣCᵢ×Vᵢ) / A Wherein, Ct is the concentration of the receiver solution at time t (μg / mL), V is the volume of the receiver cell (mL), Vi is the volume of each sample (mL), and A is the diffusion area (cm²).

[0060] Steady-state permeation rate (Jss, μg / cm²·h): The cumulative permeation amount was plotted against time, and the slope of the linear part (6-24 hours) was taken as the steady-state permeation rate, reflecting the efficiency of drug permeation through the skin.

[0061] Experimental results and analysis Table 1 Cumulative permeation amount From the cumulative permeation amount in Table 1, it can be seen that the cumulative permeation amount of galantamine hydrobromide transdermal patches corresponding to the examples was always higher than that of the comparative examples during the entire observation period, indicating that the process of drug permeation into the receiver system was more efficient and sufficient.

[0062] According to the cumulative permeation amount data in the experimental results from 6 to 24 hours, the slope of the cumulative permeation amount with respect to time in this time period was calculated to obtain the steady-state permeation rate (Jss) of each example 1-3 and comparative example 1-6, as follows: Table 2 Steady-state permeation rate The steady state permeation rate represents the rate of drug permeating through the skin into the body and reaching a steady state, which directly reflects whether the transdermal patch can continuously and stably deliver an effective dose of drug into the body. Table 2 shows that the steady state permeation rates of Examples 1-3 are all higher than those of Comparative Examples 1-6, fully embodying the significant effect of the penetration enhancer combination (azone, 2,6-nonadienol, L-lysine) and the optimized preparation process (such as cold storage treatment) in the present application on improving the transdermal efficiency of galanthamine hydrobromide.

Claims

1. A transdermal patch of galanthamine hydrobromide, characterized in that, The galanthamine hydrobromide transdermal patch has a formula comprising 1.0-4.0% galanthamine hydrobromide, a penetration enhancer combination, 60.0-70.0% pressure-sensitive adhesive matrix, 0.08-0.12% antioxidant, and solvent to 100%, wherein the penetration enhancer combination comprises azone, 2,6-nonadienol, and L-lysine.

2. The galantamine hydrobromide transdermal patch as set forth in claim 1, wherein the patch is prepared by coating a backing layer with a pressure-sensitive adhesive layer, and then coating the pressure-sensitive adhesive layer with a drug-containing layer. The pressure-sensitive adhesive matrix is solvent-type acrylate.

3. The galantamine hydrobromide transdermal patch as set forth in claim 1, wherein the patch is prepared by coating a backing layer with a pressure-sensitive adhesive layer, and then coating the pressure-sensitive adhesive layer with a drug layer. The solvent is an ethanol-ethyl acetate mixture.

4. The galantamine hydrobromide transdermal patch as set forth in claim 1, wherein the patch is prepared by coating a backing layer with a pressure-sensitive adhesive layer, and then coating the pressure-sensitive adhesive layer with a drug layer, and further coating the drug layer with a release liner. The antioxidant is at least one selected from 2,6-di-tert-butyl-p-cresol, vitamin E, and butylated hydroxyanisole.

5. The galantamine hydrobromide transdermal patch as set forth in claim 3, wherein the patch is prepared by coating a backing layer with a pressure-sensitive adhesive layer, and then coating the pressure-sensitive adhesive layer with a drug layer. The volume ratio of ethanol to ethyl acetate in the ethanol-ethyl acetate mixture is 1:

1.

6. The galantamine hydrobromide transdermal patch as set forth in claim 3, wherein the patch is prepared by coating a backing layer with a pressure-sensitive adhesive layer, and then coating the pressure-sensitive adhesive layer with a drug layer. The penetration enhancer combination comprises 2.5-3.5% azone, 1.0-2.5% 2,6-nonadienol, and 1.0-1.5% L-lysine.

7. The galantamine hydrobromide transdermal patch as set forth in claim 3, wherein the patch is prepared by coating a backing layer with a pressure-sensitive adhesive layer, and then coating the pressure-sensitive adhesive layer with a drug layer. The penetration enhancer combination comprises 3.0% azone, 1.5% 2,6-nonadienol, and 1.2% L-lysine.

8. A process for preparing the transdermal patch of galantamine hydrobromide according to claim 1, characterized in that, The preparation method comprises: (1) preparing the matrix adhesive solution by adding an appropriate amount of solvent to the solvent-type acrylate pressure-sensitive adhesive, stirring, and adding the antioxidant and stirring; (2) preparing the drug-penetration enhancer solution by adding azone, 2,6-nonadienol, and L-lysine to the solvent, stirring until dissolved, refrigerating, adding galanthamine hydrobromide, ultrasonically dissolving, and microfiltrating to obtain the drug-penetration enhancer solution; (3) preparing the drug-adhesive mixture by mixing the matrix adhesive solution and the drug-penetration enhancer solution under vacuum, vacuum degassing, and obtaining the drug-adhesive mixture; (4) coating and composite molding.

9. The production method according to claim 8, wherein The refrigeration is refrigeration at 2-8℃ for 1-3 hours.

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