Bisoprolol long-acting percutaneous absorption patch and preparation method thereof

Abstract

The invention relates to a bisoprolol long-acting transdermal absorption patch, and belongs to the technical field of medicines. The percutaneous absorption patch disclosed by the invention is suitable for being applied for three days, and consists of a backing layer, a medicine-carrying pressure-sensitive adhesive layer and an anti-sticking layer. The drug-loading pressure-sensitive adhesive layer comprises a bisoprolol organic acid ion pair compound, a pressure-sensitive adhesive and a percutaneous absorption enhancer. Wherein the weight of the bisoprolol organic acid ion pair compound accounts for 5-45wt% of the total weight of the medicine-carrying pressure-sensitive adhesive layer, the weight of the pressure-sensitive adhesive accounts for 50-90wt% of the total weight of the pressure-sensitive adhesive layer, and the dosage of the percutaneous absorption enhancer accounts for 1-20wt% of the total weight of the pressure-sensitive adhesive layer. Wherein in the bisoprolol organic acid ion pair compound, the molar ratio of bisoprolol free alkali to different organic acids is (0.5: 1)-(2: 1). The patch is simple in preparation technology and low in cost, realizes constant-speed drug release, provides a continuous treatment effect of at least three days, and is beneficial to control of symptoms and disease progression; and the method is safe, effective, good in stability and convenient to use.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a long-acting bisoprolol transdermal absorption patch, its preparation method, and its application. Background Technology

[0002] Hypertension is defined as a sustained pressure exerted by blood on the walls of blood vessels that is higher than normal as blood flows through them. According to the "Chinese Hypertension Clinical Practice Guidelines," the diagnostic criteria for hypertension in adults are a systolic blood pressure ≥130 mmHg and / or a diastolic blood pressure ≥80 mmHg. Typical symptoms include headache, fatigue, restlessness, arrhythmia, palpitations, and tinnitus. However, many patients may be asymptomatic or have developed other serious complications, such as stroke, blurred vision, loss of consciousness, and memory loss. As the leading cause of chronic cardiovascular disease globally, hypertension affects the health of nearly one billion people worldwide. According to the latest "2019 China Cardiovascular Health and Disease Report" released by the National Center for Cardiovascular Disease Prevention and Control, the prevalence of cardiovascular disease in China continues to rise. In 2020, the number of people with cardiovascular disease is expected to reach 330 million, of which 245 million are hypertensive patients, accounting for 74.2%, and the trend towards younger onset is significant. The prevalence of hypertension among Chinese adults is 27.9%, with even higher rates in rural areas. The market for drugs to treat primary hypertension in my country has shown steady growth. From 2013 to 2019, sales increased from RMB 43.4 billion to RMB 84.08 billion, with a compound annual growth rate of approximately 11.7%. It is projected that by 2026, the market size will reach RMB 154.701 billion, with a compound annual growth rate of 9.1%.

[0003] Currently, commonly used antihypertensive drugs can be broadly classified into five categories: diuretics, beta-blockers (β-blockers), calcium channel blockers (dihydropyridines), angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II receptor antagonists (ARBs). Calcium channel blockers and angiotensin II receptor antagonists account for 47.5% and 37.9% of the overall market share, respectively. Compared to diuretics, beta-blockers control blood pressure without lowering serum potassium levels, making them more suitable for long-term use in some patients. Compared to some calcium channel blockers, beta-blockers offer stronger cardioprotective effects. Furthermore, compared to angiotensin II receptor antagonists, beta-blockers may be more suitable for certain patient groups, particularly those with cardiovascular disease or arrhythmias. Bisoprolol is a beta-1 receptor blocker. It selectively works by blocking the connection between adrenaline and beta-1 receptors without affecting beta-2 receptors. Compared to metoprolol, bisoprolol has advantages such as lower dosage, fewer administrations, and higher bioavailability.

[0004] Currently, the bisoprolol dosage forms available in the domestic market are limited to tablets and capsules. Considering that many hypertension patients are elderly, once-daily oral administration is difficult to swallow and can easily lead to missed doses or duplicate doses. Therefore, developing a new bisoprolol dosage form that can maintain a therapeutic dose and stably control blood pressure is of great significance in meeting the needs of elderly patients.

[0005] Transdermal delivery systems (TDDS) are a novel type of drug delivery system that offers numerous advantages, including avoiding the adverse reactions and first-pass effect of oral administration, stable blood drug concentrations, ease of use, the ability to interrupt dosing at any time, and sustained-release properties. Toaeiyo Co., Ltd. of Japan first launched bisoprolol transdermal patches in Japan on June 28, 2013, under the brand name Bissono Tape. These patches are administered once daily and are currently available in 2mg, 4mg, and 8mg strengths for the treatment of mild to moderate essential hypertension or atrial fibrillation. The updated formulation in 2019 consists of bisoprolol free base, 2-ethylhexyl acrylate·1-vinyl-2-pyrrolidone·N-(2-hydroxyethyl)acrylamide copolymer, butyl methacrylate·methyl methacrylate copolymer, and isopropyl myristate.

[0006] Compared to traditional oral medications, long-acting patches offer a more convenient treatment option. Hypertension is a chronic condition requiring long-term management, and compared to once-daily short-acting patches, long-acting patches help maintain stable blood drug concentrations through continuous and stable drug release, thus achieving long-term blood pressure control. This continuous release not only improves patient convenience and adherence, reducing the likelihood of missed doses, but also helps reduce the occurrence of gastrointestinal side effects. For patients with swallowing difficulties or intolerance to oral medications, long-acting patches may be a safer and more convenient option. Choosing long-acting patches as a treatment method not only helps maintain stable blood pressure control but also improves patient convenience and comfort.

[0007] Therefore, it is of great significance to develop a long-acting transdermal patch for bisoprolol to meet clinical needs. Summary of the Invention

[0008] In view of this, the object of the present invention is to provide a long-acting transdermal patch for bisoprolol, with controlled release over a period of three days.

[0009] Another objective of this invention is to provide a method for preparing and applying a long-acting bisoprolol transdermal absorption patch.

[0010] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0011] The bisoprolol long-acting transdermal absorption patch of the present invention comprises a backing layer, a drug-loaded pressure-sensitive adhesive layer, and an anti-adhesive layer. Its characteristic feature is that the drug-loaded pressure-sensitive adhesive layer includes a bisoprolol organic acid ion-pair complex, a pressure-sensitive adhesive, and a transdermal absorption enhancer; wherein the total weight of the bisoprolol organic acid ion-pair complex accounts for 5-45 wt% (wt% is a weight percentage) of the total weight of the drug-loaded pressure-sensitive adhesive layer, the pressure-sensitive adhesive accounts for 50-90 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, and the transdermal absorption enhancer accounts for 1-20 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer. Preferably, the total weight of the bisoprolol organic acid ion-pair complex accounts for 10-20 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, the pressure-sensitive adhesive accounts for 75-85 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, and the transdermal absorption enhancer accounts for 5-10 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer. The organic acid in the bisoprolol organic acid ion-pair complex is a C4-C20 organic acid, preferably a C6-C12 unsaturated aliphatic organic acid.

[0012] The bisoprolol organic acid ion-pair complex mentioned therein is a pharmaceutically acceptable organic acid ion-pair complex of bisoprolol, selected from one or more of the following: benzyl sulfonic acid bisoprolol ion-pair complex, lauric acid bisoprolol ion-pair complex, maleic acid bisoprolol ion-pair complex, fumarate bisoprolol ion-pair complex, lactate bisoprolol ion-pair complex, salicylic acid bisoprolol ion-pair complex, malic acid bisoprolol ion-pair complex, n-hexanoate bisoprolol ion-pair complex, n-caprylic acid bisoprolol ion-pair complex, and n-decanoate bisoprolol ion-pair complex. Preferably, one or more of the following are selected: n-hexanoate bisoprolol ion-pair complex, maleic acid bisoprolol ion-pair complex, fumarate bisoprolol ion-pair complex, and n-caprylic acid bisoprolol ion-pair complex; most preferably, n-hexanoate bisoprolol ion-pair complex.

[0013] Bisoprolol organic acid ion-pair complexes differ from organic acid salts in that the ion-pair complexes contain hydrogen bonds, while organic acid salts are bonded by ionic bonds. Ion-pairing strategies are a simple and effective way to modify drug permeability. On the one hand, for drugs with poor skin permeability, the preparation of ion pairs can promote transdermal absorption, increase the amount of drug permeated, and improve the drug's efficacy. On the other hand, for drugs with high permeation rates, the permeation rate can be controlled to prepare long-lasting transdermal patches.

[0014] The molar ratio of bisoprolol free base to different organic acids in the bisoprolol organic acid ion-pair complex is 0.5:1 to 2:1, preferably 0.5:1, 1:1, or 2:1, and most preferably 1:1.

[0015] The bisoprolol organic acid ion-pair complex is synthesized by the following method: bisoprolol free base is dissolved in acetone, organic acid is added in proportion, the mixture is stirred at room temperature for 1-2 hours, and the solvent is evaporated to remove the bisoprolol.

[0016] The weight of the bisoprolol ion-pair complex accounts for 5% to 45% of the weight of the pressure-sensitive adhesive layer, preferably 10% to 20%.

[0017] The pressure-sensitive adhesive is one or more of polyisobutylene, silicone, polyacrylate, and polyurethane, preferably a polyacrylic acid resin pressure-sensitive adhesive, and its usage accounts for 50-90% of the total weight of the pressure-sensitive adhesive layer, more preferably 75-85% of the total weight of the drug-loaded pressure-sensitive adhesive layer. The weight of the pressure-sensitive adhesive is calculated based on its solid content.

[0018] The aforementioned polyacrylic acid resin pressure-sensitive adhesive exhibits durable skin adhesion, good water compatibility, and high drug loading and release properties. It is preferably synthesized via polymerization using a base monomer, functional monomer I, and functional monomer II. The base monomer comprises 40–80 parts, functional monomer I comprises 5–40 parts, functional monomer II comprises 0.1–20 parts, and initiator comprises 0.001–5 parts. Additionally, each step requires 200–400 parts of solvent.

[0019] The basic monomers include one or more combinations of 2-ethylhexyl acrylate, n-butyl acrylate, ethyl acrylate, dodecyl 2-acrylate, and lauryl methacrylate; the functional monomer I is selected from one or more combinations of acrylamide, N-ethylacrylamide, N-vinylpyrrolidone, and vinyl acetate; the functional monomer II includes one or more of hydroxyethyl acrylate, acrylic acid, N-hydroxyethylacrylamide, and hydroxyethyl methacrylate.

[0020] The pressure-sensitive adhesive obtained in this invention is a random copolymer. The basic monomer, as a lipophilic flexible component, provides basic adhesion to the pressure-sensitive adhesive. Functional monomers I and II, as hydrophilic rigid components, provide cohesion to the pressure-sensitive adhesive. The interaction between their special groups (e.g., hydroxyl, amide, carbonyl) and each other or between the skin can further improve the adhesion.

[0021] The initiator includes one or more of benzoyl peroxide, 2,2′-azobisisobutyronitrile, 2,2′-azobis(2,4-dimethylpentanonitrile), ammonium persulfate, and potassium persulfate.

[0022] The solvent includes one or more of ethyl acetate, acetone, methanol, ethanol, dichloromethane, and chloroform, preferably ethyl acetate. The solvent includes a solvent added during the reaction, a solvent for dissolving the initiator, and a solvent for dilution after the reaction is complete.

[0023] The present invention also provides a method for preparing the pressure-sensitive adhesive for the above-mentioned bisoprolol long-lasting transdermal absorption patch, the preparation method comprising the following steps:

[0024] (1) The basic monomer, functional monomer I and functional monomer II are added into the reactor in sequence, and solvent is added to mix the raw materials evenly;

[0025] (2) Control the temperature of the reactor between 70-80℃ and add the initiator dropwise into the reactor;

[0026] (3) After maintaining the reaction process for 10-12 hours, cool to room temperature, add diluent to dilute, and obtain the pressure-sensitive adhesive.

[0027] According to the preparation method of pressure-sensitive adhesive according to a specific embodiment of the present invention, in step (1), before the raw materials are put into the reaction vessel, the reaction vessel is filled with nitrogen or argon.

[0028] Preferably, the present invention provides a method for preparing the pressure-sensitive adhesive described above, comprising the following steps:

[0029] (1) Weigh the required raw materials according to the formula;

[0030] (2) Fill the reactor with nitrogen or argon.

[0031] (3) Add the basic monomer, functional monomer I and functional monomer II into the reactor in sequence, add solvent, start stirring, and mix the raw materials evenly.

[0032] (4) Dissolve the initiator in a solvent and place it in a constant pressure funnel;

[0033] (5) Control the temperature of the reactor between 70-80℃, open the constant pressure funnel, and add the initiator solution dropwise into the reactor. All the solution is completely added within 1-5 hours.

[0034] (6) After maintaining the reaction process for 10-12 hours, cool to room temperature, add diluent to reduce the solid content of the pressure-sensitive adhesive matrix, and finally obtain the pressure-sensitive adhesive.

[0035] According to the preparation method of pressure-sensitive adhesive according to a specific embodiment of the present invention, in step (2), the initiator is selected from one or more of benzoyl peroxide, 2,2′-azobisisobutyronitrile, 2,2′-azobis(2,4-dimethylpentanonitrile), ammonium persulfate and potassium persulfate.

[0036] Preferably, the initiator is 0.001-5 parts, and the solvent for dissolving the initiator is 10-100 parts;

[0037] According to the preparation method of pressure-sensitive adhesive according to a specific embodiment of the present invention, the solvent, including the reaction solvent in step (1), the solvent for dissolving the initiator in step (2), and the dilution solvent in step (3), is selected from one or more of ethyl acetate, acetone, methanol, ethanol, dichloromethane, and trichloromethane, preferably ethyl acetate.

[0038] Preferably, the diluent is 50-150 parts by weight.

[0039] Preferably, the present invention provides a pressure-sensitive adhesive suitable for bisoprolol long-lasting transdermal absorption patches, which is prepared from the following raw materials in parts by weight:

[0040] Basic monomer: 40-80 parts of 2-ethylhexyl acrylate;

[0041] Functional monomer I: 5-40 parts of N-vinylpyrrolidone;

[0042] Functional monomer II: 0.1-20 parts of N-hydroxyethylacrylamide;

[0043] Initiator 0.1-5 parts: selected from one or more of benzoyl peroxide, 2,2′-azobisisobutyronitrile, 2,2′-azobis(2,4-dimethylpentanonitrile), ammonium persulfate and potassium persulfate; preferably 2,2′-azobisisobutyronitrile;

[0044] In addition, it also includes solvent I 50-200 parts: selected from one or more of ethyl acetate, acetone, methanol, ethanol, dichloromethane and trichloromethane; preferably ethyl acetate;

[0045] Solvent II 10-50 parts: selected from one or more of ethyl acetate, acetone, methanol, ethanol, dichloromethane, and chloroform; preferably ethyl acetate;

[0046] Solvent III 50-150 parts: selected from one or more of ethyl acetate, acetone, methanol, ethanol, dichloromethane, and chloroform; preferably ethyl acetate;

[0047] The preparation method of the above pressure-sensitive adhesive is as follows:

[0048] The basic monomer 2-ethylhexyl acrylate, functional monomer I N-vinylpyrrolidone, and functional monomer II N-hydroxyethylacrylamide were added to a reaction vessel and mixed. Solvent I was added, and the temperature was controlled at 70-80℃. The initiator was mixed with solvent II and placed in a constant pressure funnel. It was slowly dripped into the reaction vessel over 2 hours and reacted for 10 hours. Then solvent III was added and stirred evenly to obtain a durable skin-adhesive polyacrylate pressure-sensitive adhesive.

[0049] Further preferred, the preparation method of the above pressure-sensitive adhesive is as follows:

[0050] 66 parts of the basic monomer 2-ethylhexyl acrylate, 28 parts of functional monomer I N-vinylpyrrolidone, and 6 parts of functional monomer II N-hydroxyethylacrylamide were added to a reaction vessel and mixed. 150 parts of solvent I ethyl acetate were added, and the temperature was controlled at 74℃. 0.4 parts of initiator 2,2′-azobisisobutyronitrile were mixed with 20 parts of solvent II ethyl acetate and placed in a constant pressure funnel. The mixture was slowly dripped into the reaction vessel over 2 hours and reacted for 10 hours. Then, 50 parts of solvent III ethyl acetate were added and stirred until homogeneous to obtain a durable skin-adhesive polyacrylate pressure-sensitive adhesive.

[0051] To increase the cumulative permeation of the drug in the patch, different transdermal absorption enhancers can be added. These transdermal absorption enhancers include one or more of the following: higher fatty alcohols, fatty acids, fatty acid esters, lactams, hydrocarbons, silicones, surfactants, and terpenes. The amount used is 1% to 20% of the total weight of the pressure-sensitive adhesive layer, preferably 5-10%.

[0052] Further, the transdermal absorption enhancer is azone, menthol, Span 60, Span 80, Tween 80, isopropyl myristate, oleic acid, caprylic / capric acid, polyethylene glycol glyceride, polyglycerol oleate (… One or more of Oleique CC497 and propylene glycol, preferably isopropyl myristate.

[0053] The backing layer is made of one of the following materials: polyethylene composite film, ethylene / vinyl acetate copolymer film, polyurethane film, polyester composite film, or nonwoven fabric.

[0054] The anti-stick layer is made of one of the following materials: a surface treated with silicone oil for anti-sticking, a fluorinated polyester film, or a fluoropolymer-coated polyester film.

[0055] The preparation method of the bisoprolol long-acting transdermal absorption patch is characterized by: dissolving the bisoprolol organic acid ion pair complex in an organic solvent, adding a transdermal absorption enhancer, stirring thoroughly at a uniform speed to evenly disperse the drug in a pressure-sensitive adhesive, coating it onto an anti-adhesive layer, drying it at 45–85°C for 5–25 min, covering it with a backing layer, and die-cutting to obtain the patch. The thickness of the drug-loaded pressure-sensitive adhesive is 40–180 μm.

[0056] Within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, further details are omitted here.

[0057] Beneficial effects

[0058] The bisoprolol long-acting transdermal absorption patch provided by this invention uses a bisoprolol organic acid ion-pair complex to replace the free bisoprolol base in the drug-loaded pressure-sensitive adhesive layer, and employs a self-synthesized polyacrylic acid pressure-sensitive adhesive to increase drug loading and high drug release. Simultaneously, a transdermal absorption enhancer is used to improve the transdermal permeability of bisoprolol, thus obtaining a bisoprolol long-acting transdermal absorption patch that achieves both the target dose and a constant rate of transdermal penetration. Experimental results show that the cumulative permeation of bisoprolol over 72 hours can reach 681.59 μg / cm³. 2 .

[0059] In addition, this patch is simple to prepare, inexpensive, releases drugs at a constant rate, is safe and effective, has good stability, and is easy to use. Attached Figure Description

[0060] Figure 1 Examples 15-21 are screenings of ion-pair complex types for bisoprolol ion-pair complex transdermal absorption patches based on cumulative permeation.

[0061] Figure 2 Examples 22-32 are screenings of pressure-sensitive adhesive types for bisoprolol long-acting transdermal absorption patches based on cumulative permeation.

[0062] Figure 3 Examples 33-38 are screenings of transdermal absorption enhancers for bisoprolol long-acting transdermal absorption patches based on cumulative permeation.

[0063] Figure 4 Examples 38 and 39 are in vitro transdermal experiments conducted on the bisoprolol long-acting transdermal absorption patch and a commercially available patch;

[0064] Figure 5 The blood drug concentration-time curves in rabbits for Example 38 and the commercially available patch are shown. Detailed Implementation

[0065] The present invention is illustrated in more detail through the following examples. It should be understood that the present invention is by no means limited to the embodiments, or is only exemplified by the embodiments. Conventional changes, additions, and modifications to the elements of the embodiments without departing from the spirit of the present invention are still within the protection scope of the present invention.

[0066] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0067] the term

[0068] In this invention, the terms "containing," "comprising," or "including" indicate that various ingredients may be used together in the mixtures or compositions of this invention. Therefore, the terms "consistent with..." and "composed of..." are included in the term "containing."

[0069] In this invention, the term "pharmaceuticalally acceptable" refers to a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., a substance with a reasonable benefit / risk ratio.

[0070] In this invention, unless otherwise specified, wt%, percentage, proportion, and number of parts are calculated by weight.

[0071] In this invention, the backing layer used is not particularly limited, as long as it can be used as a backing layer for adhesives. Preferred materials include polyethylene composite film, ethylene / vinyl acetate copolymer film, polyurethane film, polyester composite film, or non-woven fabric.

[0072] There are no particular limitations on the anti-adhesive layer used; any anti-adhesive layer commonly used in adhesive patches can be used. Preferably, the surface is treated with silicone oil for anti-adhesion or is a fluorinated polyester film or a fluoropolymer-coated polyester film.

[0073] Used The series of commercially available pressure-sensitive adhesives are pressure-sensitive adhesive products from Henkel, Germany.

[0074] The method for determining the solid content of pressure-sensitive adhesives is as follows:

[0075] Weigh 1g of pressure-sensitive adhesive solution, place it in a petri dish, and dry it at 60℃ for 12h. Measure the weight m after drying, and the solid content is m*100%.

[0076] Preparation Example

[0077] Preparation of bisoprolol ion-pair complexes in Examples 1-6

[0078] Example 1

[0079] Dissolve 0.1 mol of bisoprolol free base in 100 ml of acetone, add 0.1 mol of benzenesulfonic acid while stirring, continue stirring for 2 hours, and then evaporate the solvent by rotary evaporation to obtain the benzenesulfonic acid bisoprolol ion-pair complex.

[0080] Example 2

[0081] Dissolve 0.1 mol of bisoprolol free base in 100 ml of acetone, add 0.1 mol of octanoic acid while stirring, continue stirring for 2 hours, and then evaporate the solvent by rotary evaporation to obtain the octanoic acid-bisoprolol ion-pair complex.

[0082] Example 3

[0083] Dissolve 0.1 mol of bisoprolol free base in 100 ml of acetone, add 0.1 mol of lauric acid while stirring, continue stirring for 2 hours, and then evaporate the solvent by rotary evaporation to obtain the lauric acid-bisoprolol ion-pair complex.

[0084] Example 4

[0085] Dissolve 0.1 mol of bisoprolol free base in 100 ml of acetone, add 0.1 mol of maleic acid while stirring, continue stirring for 2 hours, and then evaporate the solvent by rotary evaporation to obtain the lactate bisoprolol ion-pair complex.

[0086] Example 5

[0087] Dissolve 0.1 mol of bisoprolol free base in 100 ml of acetone, add 0.1 mol of fumaric acid while stirring, continue stirring for 2 hours, and then evaporate the solvent by rotary evaporation to obtain the bisoprolol hexanoate ion-pair complex.

[0088] Example 6

[0089] Dissolve 0.1 mol of bisoprolol free base in 100 ml of acetone, add 0.1 mol of hexanoic acid while stirring, continue stirring for 2 hours, and evaporate the solvent by rotary evaporation to obtain the salicylic acid bisoprolol ion-pair complex.

[0090] Preparation of pressure-sensitive adhesive in Examples 7-14

[0091] Example 7

[0092] The reaction vessel was filled with nitrogen. 54 parts of 2-ethylhexyl acrylate, 26 parts of N-ethylacrylamide, and 20 parts of hydroxyethyl acrylate were added to the reaction vessel and mixed. 150 parts of methanol were added, and the temperature was controlled at 73°C. 0.5 parts of the initiator 2,2'-azobisisobutyronitrile were mixed with 60 parts of methanol and placed in a constant pressure funnel. The mixture was slowly added dropwise to the reaction vessel over 3 hours. The reaction was allowed to proceed for 12 hours, and then 100 parts of methanol were added and stirred until homogeneous, yielding a durable, skin-adhesive, water-compatible polyacrylate pressure-sensitive adhesive. The solid content was 32.3%.

[0093] Example 8

[0094] The reaction vessel was filled with nitrogen. 60 parts of ethyl acrylate, 30 parts of N-vinylpyrrolidone, and 10 parts of acrylic acid were added to the reaction vessel and mixed. 150 parts of ethyl acetate were added, and the temperature was controlled at 80°C. 0.4 parts of the initiator 2,2′-azobis(2,4-dimethylpentanonitrile) were mixed with 50 parts of ethyl acetate and placed in a constant pressure funnel. The mixture was slowly added dropwise to the reaction vessel over 1 hour, and the reaction was allowed to proceed for 24 hours. Then, 100 parts of ethyl acetate were added and stirred until homogeneous, yielding a durable, skin-adhesive, water-compatible polyacrylate pressure-sensitive adhesive. The solid content was 31.5%.

[0095] Example 9

[0096] The reaction vessel was filled with nitrogen. 60 parts of monomer 2-dodecyl acrylate, 30 parts of N-vinylpyrrolidone, and 10 parts of acrylamide were added to the reaction vessel and mixed. 150 parts of ethyl acetate were added, and the temperature was controlled at 80°C. 0.4 parts of initiator 2,2'-azobis(2,4-dimethylpentanonitrile) were mixed with 50 parts of ethyl acetate and placed in a constant pressure funnel. The mixture was slowly added dropwise to the reaction vessel over 1 hour, and the reaction was allowed to proceed for 24 hours. Then, 100 parts of ethyl acetate were added and stirred until homogeneous, yielding a durable, skin-adhesive, water-compatible polyacrylate pressure-sensitive adhesive. The solid content was 37.1%.

[0097] Example 10

[0098] The reaction vessel was filled with nitrogen. 66 parts of monomer 2-ethylhexyl acrylate, 28 parts of N-vinylpyrrolidone, and 6 parts of N-hydroxyethylacrylamide were added to the reaction vessel and mixed. 150 parts of ethyl acetate were added, and the temperature was controlled at 74°C. 0.4 parts of initiator 2,2′-azobisisobutyronitrile were mixed with 20 parts of ethyl acetate and placed in a constant pressure funnel. The mixture was slowly added dropwise to the reaction vessel over 2 hours. The reaction was allowed to proceed for 10 hours, and then 50 parts of ethyl acetate were added and stirred until homogeneous, yielding a durable, skin-adhesive, water-compatible polyacrylate pressure-sensitive adhesive. The solid content was 33.6%.

[0099] Example 11

[0100] The reaction vessel was filled with nitrogen. 64 parts of n-butyl acrylate, 24 parts of N-vinylpyrrolidone, and 12 parts of hydroxyethyl acrylate were added to the reaction vessel and mixed. 120 parts of ethyl acetate were added, and the temperature was controlled at 74°C. 0.4 parts of the initiator 2,2′-azobisisobutyronitrile were mixed with 20 parts of ethyl acetate and placed in a constant pressure funnel. The mixture was slowly added dropwise to the reaction vessel over 2 hours, and the reaction was allowed to proceed for 12 hours. Then, 40 parts of ethyl acetate were added and stirred until homogeneous, yielding a durable, skin-adhesive, water-compatible polyacrylate pressure-sensitive adhesive. The solid content was 34.2%.

[0101] Example 12

[0102] The reaction vessel was filled with nitrogen. 40 parts of lauryl methacrylate, 20 parts of N-vinylpyrrolidone, and 40 parts of hydroxyethyl methacrylate were added to the reaction vessel and mixed. 150 parts of ethyl acetate were added, and the temperature was controlled at 76°C. 0.5 parts of benzoyl peroxide were mixed with 20 parts of ethyl acetate and placed in a constant pressure funnel. The mixture was slowly added dropwise to the reaction vessel over 1 hour. The reaction was allowed to proceed for 24 hours. Then, 70 parts of ethyl acetate were added and stirred until homogeneous, yielding a durable, skin-adhesive, water-compatible polyacrylate pressure-sensitive adhesive. The solid content was 28.5%.

[0103] Example 13

[0104] The reaction vessel was filled with nitrogen. 40 parts of monomer 2-ethylhexyl acrylate, 50 parts of N-vinylpyrrolidone, and 10 parts of N-hydroxyethylacrylamide were added to the reaction vessel and mixed. 150 parts of ethyl acetate were added, and the temperature was controlled at 74°C. 0.4 parts of initiator 2,2′-azobisisobutyronitrile were mixed with 20 parts of ethyl acetate and placed in a constant pressure funnel. The mixture was slowly added dropwise to the reaction vessel over 2 hours. The reaction was allowed to proceed for 10 hours. Then, 50 parts of ethyl acetate were added and stirred until homogeneous, yielding a durable, skin-adhesive, water-compatible polyacrylate pressure-sensitive adhesive. The solid content was 31.3%.

[0105] Example 14

[0106] The reaction vessel was filled with nitrogen. 70 parts of monomer 2-ethylhexyl acrylate, 10 parts of N-vinylpyrrolidone, and 20 parts of N-hydroxyethylacrylamide were added to the reaction vessel and mixed. 150 parts of ethyl acetate were added, and the temperature was controlled at 74°C. 0.4 parts of initiator 2,2′-azobisisobutyronitrile were mixed with 20 parts of ethyl acetate and placed in a constant pressure funnel. The mixture was slowly added dropwise to the reaction vessel over 2 hours. The reaction was allowed to proceed for 10 hours. Then, 50 parts of ethyl acetate were added and stirred until homogeneous, yielding a durable, skin-adhesive, water-compatible polyacrylate pressure-sensitive adhesive. The solid content was 32.8%.

[0107] Examples 15-21: Preparation of Bisoprolol Transdermal Absorption Patch - Investigation of Different Ion Pair Complexes

[0108] Example 15

[0109] 0.325 g (1 mmol) of bisoprolol free base was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10, solid content 33.6%, the same below), mixed thoroughly, and evenly coated on the release layer. After drying at 50°C for 20 min, it was covered with a backing material including PVC or non-woven fabric, and die-cut to make a patch with a thickness of 65 μm.

[0110] Example 16

[0111] 0.484 g (1 mmol) of bisoprolol benzenesulfonic acid ion-pair complex (Example 1) was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and thoroughly mixed. The mixture was then evenly coated onto an anti-adhesive layer, dried at 50°C for 20 min, covered with a backing material including PVC or non-woven fabric, and die-cut to produce a patch with a thickness of 65 μm.

[0112] Example 17

[0113] 0.450 g (1 mmol) of bisoprolol octanoate ion-pair complex (Example 2) was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and thoroughly mixed. The mixture was then evenly coated onto an anti-adhesive layer, dried at 50°C for 20 min, covered with a backing material including PVC or non-woven fabric, and die-cut to produce a patch with a thickness of 65 μm.

[0114] Example 18

[0115] 0.526 g (1 mmol) of bisoprolol laurate ion-pair complex (Example 3) was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and thoroughly mixed. The mixture was then evenly coated onto an anti-adhesive layer, dried at 50°C for 20 min, covered with a backing material including PVC or non-woven fabric, and die-cut to produce a patch with a thickness of 65 μm.

[0116] Example 19

[0117] 0.442 g (1 mmol) of bisoprolol maleate ion-pair complex (Example 4) was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and thoroughly mixed. The mixture was then evenly coated onto an anti-adhesive layer, dried at 50°C for 20 min, covered with a backing material including PVC or non-woven fabric, and die-cut to produce a patch with a thickness of 65 μm.

[0118] Example 20

[0119] 0.442 g (1 mmol) of bisoprolol fumarate ion-pairing complex (Example 5) was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and thoroughly mixed. The mixture was then evenly coated onto an anti-adhesive layer, dried at 50°C for 20 min, covered with a backing material including PVC or non-woven fabric, and die-cut to produce a patch with a thickness of 65 μm.

[0120] Example 21

[0121] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pair complex (Example 6) was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and thoroughly mixed. The mixture was then evenly coated onto an anti-adhesive layer, dried at 50°C for 20 min, covered with a backing material including PVC, and die-cut to produce a patch with a thickness of 65 μm.

[0122] Examples 22-32: Preparation of Bisoprolol Transdermal Absorption Patches - Investigation of Different Types of Pressure-Sensitive Adhesives

[0123] Example 22

[0124] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 1.68 g of acrylate pressure-sensitive adhesive. Mix thoroughly in 87-4098 (solid content 40.1%), apply evenly to the release layer, dry at 50°C for 20 minutes, then cover with a backing material including PVC or non-woven fabric, and punch-cut to produce a patch with a thickness of 65μm.

[0125] Example 23

[0126] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 1.76 g of acrylate pressure-sensitive adhesive. Mix thoroughly in 87-2287 (solid content 38.2%), apply evenly to the release layer, dry at 50℃ for 20 minutes, then cover with backing material, and die-cut to make a patch with a thickness of 65μm.

[0127] Example 24

[0128] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 1.59 g of acrylate pressure-sensitive adhesive. Mix thoroughly in 87-2510 (solid content 42.2%), apply evenly to the release layer, dry at 50℃ for 20 min, then cover with backing material, and die-cut to make a patch with a thickness of 65μm.

[0129] Example 25

[0130] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 2.08 g of acrylate pressure-sensitive adhesive (32.3% solid content in Example 7), mixed thoroughly, and evenly coated onto the release liner. After drying at 50°C for 20 min, it was covered with a backing material and die-cut to produce a patch with a thickness of 65 μm.

[0131] Example 26

[0132] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 2.13 g of polyacrylate pressure-sensitive adhesive (31.5% solid content in Example 8), mixed thoroughly, and evenly coated onto the release liner. After drying at 50°C for 20 min, it was covered with a backing material and die-cut to produce a patch with a thickness of 65 μm.

[0133] Example 27

[0134] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 1.81 g of polyacrylate pressure-sensitive adhesive (37.1% solid content in Example 9), mixed thoroughly, and evenly coated onto the release liner. After drying at 50°C for 20 min, it was covered with a backing material and die-cut to produce a patch with a thickness of 65 μm.

[0135] Example 28

[0136] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and thoroughly mixed. The mixture was then evenly coated onto the release layer, dried at 50°C for 20 min, covered with a backing material, and die-cut to produce a patch with a thickness of 65 μm.

[0137] Example 29

[0138] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 1.96 g of polyacrylate pressure-sensitive adhesive (34.2% solid content in Example 11), thoroughly mixed, and uniformly coated onto an anti-adhesive layer. After drying at 50°C for 20 min, it was covered with a backing material and die-cut to produce a patch with a thickness of 65 μm.

[0139] Example 30

[0140] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 2.36 g of polyacrylate pressure-sensitive adhesive (28.5% solid content in Example 12), mixed thoroughly, and evenly coated onto the release liner. After drying at 50°C for 20 min, it was covered with a backing material and die-cut to produce a patch with a thickness of 65 μm.

[0141] Example 31

[0142] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 2.15 g of polyacrylate pressure-sensitive adhesive (31.3% solid content in Example 13), mixed thoroughly, and evenly coated onto the release liner. After drying at 50°C for 20 min, it was covered with a backing material and die-cut to produce a patch with a thickness of 65 μm.

[0143] Example 32

[0144] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 2.04 g of polyacrylate pressure-sensitive adhesive (32.8% solid content in Example 14), mixed thoroughly, and evenly coated onto the release liner. After drying at 50°C for 20 min, it was covered with a backing material and die-cut to produce a patch with a thickness of 65 μm.

[0145] Examples 33-39: Preparation of Bisoprolol Transdermal Absorption Patches; Investigation of Different Types of Transdermal Absorption Enhancers

[0146] Example 33

[0147] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and thoroughly mixed. 0.1 g of polyglycerol oleate was then added. After thoroughly mixing Oleique CC497, it is evenly coated onto the release layer, dried at 50°C for 20 minutes, covered with backing material, and die-cut to produce a patch with a thickness of 120μm.

[0148] Example 34

[0149] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and mixed thoroughly. 0.1 g of oleic acid was added and after thorough mixing, it was evenly coated on the release layer. After drying at 50°C for 20 min, it was covered with backing material and die-cut to make a patch with a thickness of 120 μm.

[0150] Example 35

[0151] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and mixed thoroughly. 0.1 g of Span-80 was added and after thorough mixing, it was evenly coated on the release layer. After drying at 50°C for 20 min, it was covered with backing material and die-cut to make a patch with a thickness of 120 μm.

[0152] Example 36

[0153] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and mixed thoroughly. 0.1 g of azone was added and after thorough mixing, it was evenly coated on the release layer. After drying at 50°C for 20 min, it was covered with backing material and die-cut to make a patch with a thickness of 120 μm.

[0154] Example 37

[0155] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and mixed thoroughly. 0.1 g of menthol was added and after thorough mixing, it was evenly coated on the release layer. After drying at 50°C for 20 min, it was covered with backing material and die-cut to make a patch with a thickness of 120 μm.

[0156] Example 38

[0157] 0.442 g (1 mmol) of bisoprolol hexanoate ion-pairing complex was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and mixed thoroughly. 0.1 g of isopropyl myristate was added and after thorough mixing, it was evenly coated on the release layer. After drying at 50°C for 20 min, it was covered with backing material and die-cut to make a patch with a thickness of 120 μm.

[0158] Example 39

[0159] 0.470 g (1 mmol) of bisoprolol octanoate ion-pairing complex was dispersed in 2 g of polyacrylate pressure-sensitive adhesive (Example 10) and mixed thoroughly. 0.1 g of isopropyl myristate was added and after thorough mixing, it was evenly coated on the release layer. After drying at 50°C for 20 min, it was covered with backing material and die-cut to make a patch with a thickness of 120 μm.

[0160] Effect test

[0161] Experimental Example 1

[0162] In vitro transdermal assay: preparation of ex vivo skin. Healthy pig ear skin was collected, and the surface hair, subcutaneous fat layer, and connective tissue were removed. After washing the skin with physiological saline, the integrity of the skin was confirmed. The intact skin was then frozen and stored at -70°C for later use.

[0163] A Franz horizontal dual-chamber diffusion cell was used, with fresh pig ear skin as the transdermal barrier and pH 7.4 phosphate buffer as the receiving medium. During the experiment, the device was continuously magnetically stirred at a speed of 350–650 rpm, and the system temperature was maintained at 32°C. The cumulative permeation of the bisoprolol patch in the example was measured over 72 hours.

[0164] In the in vitro transdermal experiments, the patch area was 1.13 cm². 2 .

[0165] 1) The bisoprolol ion-pairing complex transdermal absorption patches prepared in Examples 15-21 were screened for ion-pairing complex types based on cumulative permeation and transdermal permeation rate. The results are shown in […]. Figure 1 See Table 1.

[0166] Table 1. Transdermal permeation rates of bisoprolol or its ion-pair complex at different time points

[0167]

[0168]

[0169] Conclusion: The cumulative permeation amount and permeation rate of the patch prepared after synthesizing the ion-pair complex of bisoprolol and organic acid within 72 h were lower than those of the bisoprolol free base patch (Example 15), but the flux remained relatively stable throughout the experiment. Among them, as preferred, the cumulative permeation amount of the patches of Example 19 (bisoprolol maleate ion-pair complex), Example 20 (bisoprolol fumarate ion-pair complex), and Example 21 (bisoprolol hexanoate ion-pair complex) was higher than that of Examples 16-18, and the flux remained relatively stable throughout the experiment, which can achieve the purpose of constant drug release. Considering both the cumulative permeation amount and the relative stability of flux, bisoprolol hexanoate is the most preferred ion-pair complex.

[0170] 2) The bisoprolol long-acting transdermal absorption patches prepared in Examples 22 to 32 were screened for pressure-sensitive adhesive types based on cumulative permeation. The results are shown in Table 2 and... Figure 2 .

[0171] Table 2. Cumulative in vitro permeation rates of Examples 22 to 32

[0172]

[0173] Conclusion: Example 28, which uses polyacrylate pressure-sensitive adhesive (Example 10), has the highest cumulative permeation. Therefore, polyacrylate pressure-sensitive adhesive (Example 10) is the most preferred pressure-sensitive adhesive.

[0174] 3) The types of transdermal absorption enhancers for the bisoprolol long-acting transdermal patches prepared in Examples 33 to 38 were screened based on cumulative permeation. The results are shown in Table 3 and [Table data missing]. Figure 3 .

[0175] Table 3. Cumulative in vitro permeation rates of Examples 33-38

[0176]

[0177] Conclusion: Compared with the absence of transdermal absorption enhancers (Example 28), azone, menthol, Span 80, and polyglycerol oleate ( Both Oleique CC497 and oleic acid promoted the cumulative permeation of bisoprolol to varying degrees. Among them, isopropyl myristate (IPM) (Example 38) had the most significant permeation-promoting effect compared to bisoprolol. Therefore, isopropyl myristate (IPM) is the preferred transdermal absorption promoter.

[0178] 4) Examples 38 and 39 used bisoprolol long-acting transdermal patches prepared with the optimal combination of pressure-sensitive adhesive and transdermal absorption enhancer. In vitro transdermal experiments were conducted with commercially available patches, and the results are shown in Table 4. Figure 4 .

[0179] Table 4. Cumulative in vitro permeation of Examples 38, 39 and commercially available patches

[0180]

[0181] Conclusion: The cumulative permeation of Example 38 over 72 hours was approximately three times that of commercially available patches with a constant rate of drug release. Even the non-preferred bisoprolol ion-pair complex (Example 39, bisoprolol n-octanoate ion-pair complex) achieved a cumulative permeation of 2.4 times that of commercially available patches over 72 hours. This demonstrates that the combination of the bisoprolol ion-pair complex of the present invention with polyacrylate pressure-sensitive adhesive and transdermal absorption enhancer can prepare a long-acting transdermal absorption patch with a shelf life of three days.

[0182] Experimental Example 2

[0183] Using commercially available bisoprolol transdermal absorption patches Pharmacokinetic studies were conducted on rabbits using the patch (8 mg / 24 h, Nitto Denko Corporation) and Example 38. Twelve rabbits were randomly divided into two groups. The patch was applied to the shaved abdominal area of ​​the rabbits. Blood samples were collected from the marginal ear vein at predetermined time points to determine the blood drug concentration. The patch area for Example 38 was 26.2 cm². 2 The drug content per unit area is 0.84 mg / cm². 2 The total drug content is 22mg; the patch should be removed after 72 hours. The commercially available bisoprolol transdermal absorption patch has an area of ​​35.7cm². 2 One patch per day, for a total of three patches, each patch containing 8mg of medication. Results are shown in Table 5. Figure 4 , Figure 5 .

[0184] Table 5. Pharmacokinetic parameters in rabbits for commercially available patches and Example 38

[0185]

[0186] Note: t = 72h

[0187] Conclusion: In the pharmacokinetic study of rabbits, the preferred prescription patch group (Example 38) of this invention had a drug delivery area of ​​26.2 cm². 2 Smaller than commercially available patches Patch (8mg / 24h, Nitto Denko Co., Ltd.) (35.7cm) 2 (as shown in Table 5 and...) Figure 5As shown, the plasma drug concentration in Example 38 increased slowly and then reached a plateau (12h–54h), maintaining a concentration of approximately 100 ng / mL, with a significantly prolonged absorption time. At 72h, the relative bioavailability of the Example 38 patch compared to the commercially available patch was 84.68%, with no significant difference in AUC values ​​(P > 0.05). Compared to the commercially available patch, the Tg of the Example 38 patch was significantly higher. max Delay, MRT 0-t The extended effect demonstrates that the patch in Example 38 effectively controls the absorption of bisoprolol in vivo, achieving a long-lasting, constant-rate release. Furthermore... Figure 4 As shown, the cumulative permeation over 24 hours is roughly the same, and the cumulative permeation over 72 hours is about three times that of commercially available patches. The cumulative permeation curve is almost linear. Therefore, Example 38 can reduce the frequency of administration from once a day to once every three days, thus improving patient compliance.

Claims

1. A long-acting bisoprolol transdermal patch, comprising a backing layer, a drug-loaded pressure-sensitive adhesive layer, and an anti-adhesive layer, characterized in that, The drug-loaded pressure-sensitive adhesive layer comprises a bisoprolol organic acid ion-pair complex, a pressure-sensitive adhesive, and a transdermal absorption enhancer; wherein the total weight of the bisoprolol organic acid ion-pair complex accounts for 5-45 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, the pressure-sensitive adhesive accounts for 50-90 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, and the transdermal absorption enhancer accounts for 1-20 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer; preferably, the total weight of the bisoprolol organic acid ion-pair complex accounts for 10-20 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, the pressure-sensitive adhesive accounts for 75-85 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer, and the transdermal absorption enhancer accounts for 5-10 wt% of the total weight of the drug-loaded pressure-sensitive adhesive layer.

2. The bisoprolol long-acting transdermal absorption patch according to claim 1, characterized in that, The pressure-sensitive adhesive is a water-compatible polyacrylic resin-based pressure-sensitive adhesive with long-lasting skin adhesion.

3. The bisoprolol long-acting transdermal absorption patch according to claim 1, characterized in that, The pressure-sensitive adhesive is synthesized from a base monomer, functional monomer I, and functional monomer II. The base monomer is selected from one or more of 2-ethylhexyl acrylate, n-butyl acrylate, ethyl acrylate, dodecyl 2-acrylate, and lauryl methacrylate. Functional monomer I is selected from one or more of acrylamide, N-ethylacrylamide, N-vinylpyrrolidone, and vinyl acetate. Functional monomer II is selected from one or more of hydroxyethyl acrylate, acrylic acid, N-hydroxyethylacrylamide, and hydroxyethyl methacrylate.

4. The bisoprolol long-acting transdermal absorption patch as described in claim 3, characterized in that, When synthesizing the pressure-sensitive adhesive, the amount of base monomer is 40-80 parts, the amount of functional monomer I is 5-40 parts, the amount of functional monomer II is 0.1-20 parts, and the amount of initiator is 0.001-5 parts.

5. The bisoprolol long-acting transdermal absorption patch as described in claim 3, characterized in that, The pressure-sensitive adhesive is prepared from the following raw materials in parts by weight: Basic monomer: 40-80 parts of 2-ethylhexyl acrylate; Functional monomer I: 5-40 parts of N-vinylpyrrolidone; Functional monomer II: 0.1-20 parts of N-hydroxyethylacrylamide; Initiator 0.1-5 parts: selected from one or more of benzoyl peroxide, 2,2′-azobisisobutyronitrile, 2,2′-azobis(2,4-dimethylpentanonitrile), ammonium persulfate and potassium persulfate; preferably 2,2′-azobisisobutyronitrile.

6. The bisoprolol long-acting transdermal absorption patch according to claim 1, characterized in that, The organic acid in the bisoprolol organic acid ion pair complex is a C4-C20 organic acid; preferably a C6-C12 unsaturated aliphatic organic acid; the bisoprolol organic acid ion pair complex is selected from one or more of the following: benzenesulfonic acid bisoprolol ion pair complex, lauric acid bisoprolol ion pair complex, maleic acid bisoprolol ion pair complex, fumaric acid bisoprolol ion pair complex, lactic acid bisoprolol ion pair complex, salicylic acid bisoprolol ion pair complex, malic acid bisoprolol ion pair complex, hexanoic acid bisoprolol ion pair complex, octanoic acid bisoprolol ion pair complex, and decanoic acid bisoprolol ion pair complex; more preferably, one or more of the following: hexanoic acid bisoprolol ion pair complex, maleic acid bisoprolol ion pair complex, fumaric acid bisoprolol ion pair complex, and octanoic acid bisoprolol ion pair complex; most preferably, hexanoic acid bisoprolol ion pair complex.

7. The bisoprolol long-acting transdermal patch according to claim 1 or 2, characterized in that, The bisoprolol organic acid ion-pair complex is prepared by reacting bisoprolol free base with an organic acid, wherein the molar ratio of bisoprolol free base to organic acid is 0.5:1 to 2:1, preferably 1:

1.

8. The bisoprolol long-acting transdermal absorption patch according to claim 1 or 2, characterized in that, The bisoprolol free base or its ion-pair complex accounts for 5% to 45 wt% of the weight of the pressure-sensitive adhesive, preferably 10% to 20 wt%.

9. The bisoprolol long-acting transdermal absorption patch according to claim 1 or 2, characterized in that, The transdermal absorption enhancer comprises one or more of the following compounds: higher fatty alcohols, fatty acids, fatty acid esters, lactams, hydrocarbons, silicones, surfactants, and terpenes, preferably azone, menthol, Span 60, Span 80, Tween 80, isopropyl myristate, oleic acid, PEG-3-ethylhexyl oleate, and polyglycerol oleate. One or more of CC497 and propylene glycol, with isopropyl myristate being the most preferred.

10. The method for preparing the bisoprolol long-acting transdermal absorption patch according to claim 1, characterized in that, The bisoprolol organic acid ion-pair complex is dissolved in an organic solvent, a transdermal absorption enhancer is added, and the mixture is stirred at a constant speed to ensure uniform dispersion of the drug in the pressure-sensitive adhesive. The mixture is then coated onto an anti-adhesive layer and dried at 25–85°C for 5–25 minutes. Finally, a backing layer is covered, and the mixture is die-cut to obtain the final product.

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