Transdermal patch containing cinacalcet as well as preparation method and application of transdermal patch

Abstract

The invention discloses a cinacalcet-containing transdermal patch as well as a preparation method and application thereof. The transdermal patch comprises a high-molecular matrix layer, wherein the high-molecular matrix layer comprises cinacalcet, a silicone pressure-sensitive adhesive and one or more high-molecular polymers selected from a water-insoluble cellulose derivative, polyvinylpyrrolidone and a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The transdermal patch disclosed by the invention is good in drug permeability and colloid application performance, high in safety, free of skin irritation, high in stability and good in uniformity, and can meet the requirements of clinically treating hyperparathyroidism or hypercalcemia.

Description

Technical Field

[0001] This invention belongs to the field of transdermal drug delivery technology, specifically relating to a transdermal patch containing cinacalcet, its preparation method, and its uses. Background Technology

[0002] Transdermal drug delivery systems (transdermal patches) are a method of drug administration that delivers active ingredients into the body through the skin or mucous membranes to achieve local or systemic effects. Based on the combination of the active ingredient and other excipients in the patch, patches can be broadly classified into reservoir patches and drug-in-adhesive patches. Drug-in-adhesive patches consist of an active ingredient uniformly dissolved or dispersed in a semi-solid composition of one or more polymeric materials and other pharmaceutically acceptable excipients, forming a homogeneous drug-containing polymer matrix. If the polymeric material itself is a pressure-sensitive adhesive, then the polymer matrix acts as both a drug carrier and an adhesive to the skin at the application site.

[0003] Cinacalcet has the molecular formula C 22 H 22 F3N, with a molecular weight of 357.42, is chemically named N-((1R)-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)prop-1-amine. It is a pale yellow oil. It is slightly soluble in methanol and carbon tetrachloride, and practically insoluble in water. Its chemical structural formula is as follows:

[0004] Cinacalcet is clinically indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) undergoing maintenance dialysis or hypercalcemia in patients with parathyroid carcinoma. It is an oral calcium receptor agonist (calcifying agent) that lowers parathyroid hormone (PTH) levels by increasing the sensitivity of calcium receptors to extracellular calcium. It regulates the behavior of parathyroid calcium receptors and reduces the levels of parathyroid hormone, calcium, phosphorus, and calcium-phosphorus complexes by enhancing the sensitivity of receptors to calcium levels in the bloodstream.

[0005] Currently marketed cinacalcet hydrochloride tablets often cause severe gastrointestinal reactions when administered orally, with an adverse reaction rate exceeding 50%. Medication adherence is poor, with less than 30% of patients consistently taking the medication. Cinacalcet hydrochloride tablets also have low oral bioavailability with significant individual variation, making dosage adjustment inconvenient. Developing a topical patch to replace tablets could avoid a series of adverse reactions caused by drug contact with the gastric mucosa, reduce the side effects of oral medications, and improve patient safety and adherence, offering clinical advantages.

[0006] Chinese patent application CN106806893A discloses a topical skin patch containing a calcium-sensitive receptor agonist, which includes cinacalcet hydrochloride as the active ingredient. However, research has found that the active pharmaceutical ingredient cinacalcet hydrochloride has low solubility and poor permeability in pressure-sensitive adhesive matrix materials, and the transdermal patch prepared from it cannot meet the expected permeability requirements.

[0007] Taiwanese patent application TW201628603A discloses a transdermal absorption formulation containing cinacalcet or a pharmaceutically acceptable salt thereof as the active ingredient. This patent discloses the use of a single rubber-based resin, an acrylic resin, or a polysiloxane resin, or a combination of two or more, with rubber-based resin or acrylic resin preferred as the matrix material. While acrylic resins (i.e., the acrylic pressure-sensitive adhesive described in this invention) have good solubility for cinacalcet, their drug permeability is poor, and stability tests show that impurities grow rapidly in cinacalcet patches containing high levels of acrylic pressure-sensitive adhesive, resulting in a higher stability risk. Although this patent lists polysiloxane resins (i.e., the silicone pressure-sensitive adhesive described in this invention) as one of the commonly used pressure-sensitive adhesives in its specification, it does not provide specific examples.

[0008] Silicone pressure-sensitive adhesive (PSA) is a commonly used type of PSA with advantages such as stability and low skin irritation. However, research has found that due to the significant differences in physicochemical properties between PSA and cinacalcet, their compatibility is poor. Only a small amount of cinacalcet can dissolve in the adhesive solution, resulting in a patch that cannot achieve the therapeutic effect. Increasing the cinacalcet content in the PSA, for example, to 5% or more, causes the adhesive solution to break down and solids to precipitate after mixing, making it impossible to coat and prepare the patch. This prevents further increasing the cinacalcet content in the PSA from improving the patch's permeability.

[0009] Therefore, the preparation of transdermal patches containing cinacalcet using silicone pressure-sensitive adhesives requires first addressing the compatibility issue between cinacalcet and the silicone pressure-sensitive adhesive, and further improving drug loading and permeability. In addition, it is necessary to address issues such as poor patch adhesion at high drug concentrations to meet clinical treatment needs. Summary of the Invention

[0010] Therefore, the object of this invention is to provide a transdermal patch containing cinacalcet and silicone pressure-sensitive adhesive, its preparation method, and its uses. This invention solves the problems of poor compatibility between cinacalcet and silicone pressure-sensitive adhesive, and the resulting low solubility of cinacalcet in the silicone pressure-sensitive adhesive and low drug permeation. Furthermore, this invention also solves the problem of poor patch application performance at high drug concentrations. The transdermal patch of this invention has high drug permeation capacity, good application performance, high safety, no skin irritation, high stability, and good uniformity, and can meet the needs of clinical treatment.

[0011] The inventors unexpectedly discovered through research that adding one or more polymers selected from insoluble cellulose derivatives, polyvinylpyrrolidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers can improve the compatibility of cinacalcet with silicone pressure-sensitive adhesives, thereby increasing the solubility and content of cinacalcet in silicone pressure-sensitive adhesives, and significantly increasing drug release and permeation capacity. At the same time, it can also improve the problem of soft and sticky adhesive, stringing and delamination caused by high cinacalcet content, improve the product's application performance, and enhance product stability and safety, thus solving the technical problems existing in the prior art and completing this invention.

[0012] Terminology Definition : Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly used in the field to which this invention pertains. For the purposes of interpreting this specification, the following definitions will apply.

[0013] The term "transdermal patch" or "transdermal drug delivery system" as used in this invention refers to a system containing active ingredients for transdermal drug delivery, generally comprising a backing layer and a release membrane, and a polymer matrix layer located between the two layers. Based on the combination of the active ingredient and other components within the polymer matrix layer, it can generally be classified into reservoir type and gel-drug hybrid type. Transdermal drug delivery systems can also be simply referred to as patches or transdermal patches; these names are used interchangeably in this invention.

[0014] As used in this invention, the term "polymer matrix layer" refers to the material combination of a polymeric pressure-sensitive adhesive, active ingredient, and other pharmaceutically acceptable excipients included in a transdermal drug delivery system. Typically, the polymer matrix layer is located between the release film and the backing film. As the drug delivery layer of the transdermal drug delivery system, the polymer matrix layer forms a drug-adhesive hybrid transdermal drug delivery system.

[0015] The term "permeability" used in this invention refers to the passive diffusion of a drug through the skin or mucous membrane, driven by the concentration difference of the active ingredient across the skin. The cumulative permeation amount per unit time and unit area can be used as an indicator of the patch's permeability, generally denoted as Flux, with units of μg / cm². 2 / h. Alternatively, the cumulative transmittance per unit area at each time point can be used for evaluation, generally denoted as Q. t The unit is μg / cm³ 2 .

[0016] The term "application performance" as used in this invention refers to the degree of adhesion between the transdermal patch and the skin at the application site during the application process, as well as the degree of cold flow, stringing, and degumming of the drug-containing colloid.

[0017] The term "pressure-sensitive adhesive" as used in this invention refers to a class of viscoelastic polymer materials that, when in contact with most other material surfaces, can adhere to each other with very light pressure and maintain long-term adhesion. The main function of pressure-sensitive adhesives is to adhere patches to the skin for the prescribed treatment time. They also act as a polymer matrix to retain drugs and any excipients within the formulation. Pressure-sensitive adhesives possess satisfactory physical properties at room temperature, such as good skin adhesion, maintaining adhesion for a certain period, peeling without damaging the skin, and controllable cold flow, thus meeting the application requirements. Common types include acrylic pressure-sensitive adhesives, silicone pressure-sensitive adhesives, and polyisobutylene pressure-sensitive adhesives, as well as new hybrid pressure-sensitive adhesives formed by physical mixing or chemical bonding of the above-mentioned adhesives, in order to control the properties of the pressure-sensitive adhesive to meet specific requirements.

[0018] The term "silicone pressure-sensitive adhesive" as used in this invention refers to a polymer formed by the condensation reaction of low-viscosity polydimethylsiloxane and silicone resin. Silicone pressure-sensitive adhesives have a softening point close to human skin temperature and exhibit good flowability, flexibility, and adhesion at normal body temperature. They also possess characteristics such as heat and oxidation resistance, low-temperature resistance, hydrophobicity, low cohesiveness, and low drug solubility. Commercially available silicone pressure-sensitive adhesives include products from DuPont, such as Liveo™ BIO-PSA7-4101, Liveo™ BIO-PSA 7-4102, Liveo™ BIO-PSA 7-4201, Liveo™ BIO-PSA 7-4202, Liveo™ BIO-PSA 7-4301, Liveo™ BIO-PSA 7-4302, Liveo™ BIO-PSA 7-4401, Liveo™ BIO-PSA 7-4402, Liveo™ BIO-PSA 7-4501, Liveo™ BIO-PSA 7-4502, Liveo™ BIO-PSA7-4601, and Liveo™ BIO-PSA 7-4602.

[0019] The term "acrylate pressure-sensitive adhesive" as used in this invention includes dimer, trimer, and polymeric pressure-sensitive adhesives. Monomers that can be used to prepare acrylate pressure-sensitive adhesives include acrylic monomers (such as acrylic acid, acrylates, and acrylamides) and non-acrylic monomers (such as vinyl acetate). Commercially available acrylic pressure-sensitive adhesives include Henkel's Duro-Tak products, such as Duro-Tak 87-900A, Duro-Tak 87-9301, Duro-Tak 87-4098, Duro-Tak 387-2510 / 87-2510, Duro-Tak 387-2287 / 87-2287, Duro-Tak 87-2852, Duro-Tak 387-2516 / 87-2516, Duro-Tak 87-2074, Duro-Tak 87-235A, Duro-Tak 87-2194, Duro-Tak 87-2196, Duro-Tak 87-2677, and Duro-Tak... 387-2051 / 87-2051, Duro-Tak 387-2052 / 87-2052 and Duro-Tak 387-2054 / 87-2054, etc.

[0020] The term "by weight of the polymer matrix layer, ... the weight content of ..." used in this invention refers to the dry weight ratio of each component to the polymer matrix layer.

[0021] As used in this invention, the term "in-situ dissociation" refers to the fact that the cinacalcet free base in the transdermal patch is obtained during the preparation of the formulation by reacting a pharmaceutically acceptable salt of cinacalcet, used as a raw material, with a basic compound. After the reaction, the cinacalcet free base may not be separated and purified; instead, other pharmaceutically acceptable excipients may be added directly to the reaction solution system to prepare a cinacalcet-containing transdermal patch. In this case, the transdermal patch also contains the salt formed by the reaction of the basic compound with a pharmaceutically acceptable salt of cinacalcet. For example, when cinacalcet hydrochloride and sodium hydroxide are used to in-situ dissociate and generate the cinacalcet free base, and a cinacalcet-containing transdermal patch is prepared directly without separation and purification, the transdermal patch includes sodium chloride in addition to the cinacalcet free base generated in the reaction.

[0022] As used in this invention, the terms "backing layer" or "backing film" refer to the layer in a transdermal drug delivery patch that the drug cannot permeate. One surface of the backing layer is directly connected to the polymer matrix layer. During use, the backing layer protects the polymer matrix layer from contact with the surrounding environment, preventing drug loss. Materials for the backing layer generally include polyester, polyethylene-polyvinyl acetate composite film, polyvinyl chloride, polyurethane, metal foil composite film, non-woven fabric, and elastic fabric, with a thickness typically ranging from 10 to 200 μm. For example, ScotchPak from 3M can be used. TM 9730, 9701, 9720, 9723, 9733, 9754, 1109, Xiaoshan elastic fabric 6015A from China, Poring nonwoven fabric EW2080 and EW2083 from Japan, or Shanghai Yingfa PE3601, etc. The backing layer or backing film of this invention have the same meaning and are interchangeable.

[0023] The term "release film" used in this invention can also be referred to as a protective layer, which is directly bonded to the other surface of the polymer matrix layer. The release film is removed before use of the transdermal patch. For example, ScotchPak from 3M can be used. TM Release films of various specifications from Fujimori Industrial Co., Ltd., including 1022, 9709, 9744, and 9755; 75u transparent release films from Hsiang Wei Technology Co., Ltd. (Taiwan); various specifications of release films from Sinosys Co., Ltd. (Taiwan); N75 400 and 75u PET release films from Wuxi Zhongxing New Material Technology Co., Ltd.; model 5192 release film from Naiheng (Guangzhou) Paper Products Co., Ltd.; fluorinated release films from Guangdong Desheng New Material Technology Co., Ltd.; fluorinated release films from Nantong Huakai New Material Technology Co., Ltd.; pharmaceutical PET release films from Zhejiang Xili Anti-stick Paper Manufacturing Co., Ltd.; various specifications of release films from Jiangsu Shuangguan New Material Technology Co., Ltd.; polyester pharmaceutical release films from Shenyang Zhongjia Plastic Products Co., Ltd.; polyester release films from Shanghai Yingfa Medical Composite Materials Co., Ltd.; and various specifications of release films from Anhui Meikai Medical Technology Co., Ltd., etc.; as well as BD type release films from Fujimori Industrial Co., Ltd. (Japan) and LOPAREX. Silicon-coated release films include various specifications of release films produced by BV, various specifications of release films produced by Jiangsu Shuangguan New Material Technology Co., Ltd., and XL8016W type release film from Zhejiang Xili Anti-stick Paper Manufacturing Co., Ltd.

[0024] As used in this invention, the terms "through effective dose" or "through amount to achieve therapeutic effect" refer to the delivery of an active ingredient through the skin in sufficient quantities to achieve the desired local or systemic effect during the use of a transdermal patch, thereby achieving a specific pharmacological action, such as curing, alleviating, or controlling a disease or symptom. These terms are interchangeable in this invention.

[0025] The objective of this invention is achieved through the following technical solution: On one hand, the present invention provides a transdermal patch containing cinacalcet, which comprises a polymer matrix layer, wherein the polymer matrix layer comprises cinacalcet, silicone pressure-sensitive adhesive, and one or more polymers selected from water-insoluble cellulose derivatives, polyvinylpyrrolidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers.

[0026] Preferably, the polymer is a water-insoluble cellulose derivative; Preferably, the weight content of the cinakaser is 10% to 40%, the weight content of the polymer is 3% to 15%, and the weight content of the silicone pressure-sensitive adhesive is 30% to 80%, based on the weight of the polymer matrix layer.

[0027] Adding one or more polymers selected from insoluble cellulose derivatives, polyvinylpyrrolidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers to silicone pressure-sensitive adhesive systems can significantly improve the compatibility of cinacalcet with silicone pressure-sensitive adhesives and increase its solubility in the silicone pressure-sensitive adhesive. This allows the cinacalcet content in the polymer matrix layer to reach over 10%, and also improves drug permeability. Surprisingly, although insoluble cellulose derivatives, such as ethyl cellulose, have poor compatibility with silicone pressure-sensitive adhesives and form a jelly-like substance when mixed alone, making it impossible to prepare a homogeneous adhesive solution, mixing them with cinacalcet in silicone pressure-sensitive adhesives can solve the problem of incompatibility between cinacalcet and silicone pressure-sensitive adhesives, thus preventing the adhesive solution from being compromised. Furthermore, insoluble cellulose derivatives (such as ethyl cellulose) can significantly improve the compatibility of cinacalcet with silicone pressure-sensitive adhesives and increase its solubility in silicone pressure-sensitive adhesives, improving the colloidal state and viscosity, and also facilitating drug permeation. Patches prepared with the addition of insoluble cellulose derivatives (such as ethyl cellulose) exhibit significantly higher drug permeation capacity and better adhesive application performance. Simultaneously, insoluble cellulose derivatives (such as ethyl cellulose) can also improve the stringing and delamination issues when the adhesive contains a high content of cinacalcet, thus improving adhesive application performance.

[0028] In this invention, the content of each component can be any decimal or integer value within a defined range. For example, based on the weight of the polymer matrix layer, the weight content of the cinakase can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, etc.; the weight content of the polymer can be 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, etc.; and the weight content of the silicone pressure-sensitive adhesive can be 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, etc.

[0029] When the cinacalcet content is 25% to 35%, drug permeability is significantly improved. Further increasing the drug content to over 40% does not significantly increase drug permeability, and the patch risks deterioration in application performance and phase separation. Therefore, preferably, in the polymer matrix layer of the present invention, the cinacalcet content is 25% to 35% by weight, and correspondingly, the polymer content is 3% to 15% by weight, and the silicone pressure-sensitive adhesive content is 30% to 75% by weight.

[0030] Preferably, cinacalcet is generated by in-situ dissociation of a pharmaceutically acceptable salt of cinacalcet with a basic compound; preferably, the pharmaceutically acceptable salt of cinacalcet is selected from cinacalcet inorganic acid salts or cinacalcet organic acid salts, preferably one or more of cinacalcet hydrochloride, cinacalcet hydrobromide, cinacalcet sulfate, cinacalcet nitrate, cinacalcet phosphate, cinacalcet methanesulfonate, cinacalcet succinate, cinacalcet acetate, and cinacalcet ascorbate; preferably, the basic compound is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, and sodium carbonate.

[0031] The secondary amino groups present in cinacalcet are easily oxidized. To improve drug stability, currently marketed oral formulations all use its hydrochloride form. However, cinacalcet hydrochloride has very low solubility and permeability in pressure-sensitive adhesives, making it impossible to achieve the therapeutic effect. This invention generates free cinacalcet base by in-situ dissociation reaction of a pharmaceutically acceptable salt of cinacalcet with a basic compound. This reduces the generation of oxidative impurities and improves drug permeability. Another advantage of the patch containing polymers in this invention is that other excipients, such as polymers, can be added directly to the reaction solution system after the reaction without separation and purification to prepare the transdermal patch. This avoids the oxidation of the free cinacalcet base during purification and also avoids the destructive effect of the reaction solution on the adhesive. The adhesive solution is in good condition after mixing all raw materials and excipients, making it suitable for application.

[0032] Preferably, the silicone pressure-sensitive adhesive is selected from one or more of Liveo™ BIO-PSA 7-4101, Liveo™ BIO-PSA 7-4102, Liveo™ BIO-PSA 7-4201, Liveo™ BIO-PSA 7-4202, Liveo™ BIO-PSA 7-4301, Liveo™ BIO-PSA 7-4302, Liveo™ BIO-PSA 7-4401, Liveo™ BIO-PSA 7-4402, Liveo™ BIO-PSA 7-4501, Liveo™ BIO-PSA 7-4502, Liveo™ BIO-PSA 7-4601, and Liveo™ BIO-PSA 7-4602; The insoluble cellulose derivative is selected from one or more of ethyl cellulose, cellulose acetate, and cellulose acetate butyrate; preferably, the viscosity of the ethyl cellulose is 5-300 cps (USP911); preferably, the weight-average molecular weight of the ethyl cellulose is 20,000-300,000; more preferably, the ethyl cellulose is selected from one or more of ECN10, ECN50, and ECN100; and / or The polyvinylpyrrolidone is selected from one or more of PVP K30 and PVP K90.

[0033] The ethyl cellulose described in this invention is not particularly limited. Through extensive experimentation, the inventors have discovered that various common types of ethyl cellulose can achieve the objectives of this invention. For example, ethyl cellulose from different manufacturers with different viscosities and molecular weights can be selected, including but not limited to: ethyl cellulose with low viscosity grades (such as EC N10), medium viscosity grades (such as ECN50), and high viscosity grades (such as EC N100). For example, the ethyl cellulose can be selected from commercially available sources such as Ashland's EC N10, EC N50, and EC N100. The polyvinylpyrrolidone can be selected from commercially available sources such as Evonik's PVP K30 and PVP K90. The polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer can be selected from commercially available sources such as BASF's Soloplus. ® wait.

[0034] The polymer matrix layer may further contain acrylate pressure-sensitive adhesive; preferably, the weight ratio of the acrylate pressure-sensitive adhesive to the silicone pressure-sensitive adhesive is not greater than 1:1, more preferably, the weight ratio of the acrylate pressure-sensitive adhesive to the silicone pressure-sensitive adhesive is not greater than 2:3, even more preferably, the weight ratio of the acrylate pressure-sensitive adhesive to the silicone pressure-sensitive adhesive is not greater than 1:5; particularly preferably, the polymer matrix layer does not contain acrylate pressure-sensitive adhesive.

[0035] Adding acrylate pressure-sensitive adhesive to a silicone pressure-sensitive adhesive system can improve the solubility of cinacalcet in the colloid to some extent. However, the addition of acrylate pressure-sensitive adhesive significantly reduces the permeability of cinacalcet and leads to an increase in impurity content. In this invention, the weight ratio of acrylate pressure-sensitive adhesive to the silicone pressure-sensitive adhesive is preferably no greater than 1:1. Furthermore, the drug permeability is strongest when using silicone pressure-sensitive adhesive alone; therefore, this invention particularly prefers that the polymer matrix layer does not contain acrylate pressure-sensitive adhesive.

[0036] Preferably, the polymer matrix layer further comprises one or more other pharmaceutically acceptable excipients, preferably one or more of fillers, penetration enhancers and antioxidants.

[0037] Preferably, based on the weight of the polymer matrix layer, the filler content is 0.5% to 15% by weight, for example, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, etc., preferably 2% to 12%, more preferably 5% to 11%, and the penetration enhancer content is 0.1% to 20% by weight, for example, 0.1%, 0.2%, 0.5%, 0.8%, 1%, 1.2%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 1 The antioxidant content is 4%, 15%, 16%, 17%, 18%, 19%, 20%, etc., preferably 0.5% to 15%, more preferably 1% to 12%, and / or the weight content of the antioxidant is 0.01% to 1%, for example, it can be 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, etc., preferably 0.1% to 0.8%, more preferably 0.4% to 0.6%.

[0038] The adhesive viscosity can be adjusted by adding fillers to the polymer matrix layer. Cinacarpine patches containing fillers exhibit good product uniformity and stability during long-term storage.

[0039] Preferably, the filler is selected from one or more of talc, bentonite, kaolin, hydrophobic colloidal silica, and montmorillonite.

[0040] The addition of a permeation enhancer can further improve the permeation capacity of cinacalcet. Preferably, the permeation enhancer is selected from one or more of fatty alcohols, fatty alcohol amines, fatty acids, fatty acid esters, fatty ethers, dimethyl sulfoxide, and azone; preferably, the permeation enhancer is selected from C... 10 ~C 20 One or more of the following: fatty alcohols, triethanolamine, oleic acid, coconut oil ester caprylate, isopropyl palmitate, isopropyl myristate, cocoyl caprylate caprylate, ethyl oleate, triethyl citrate, glyceryl monooleate, glyceryl triacetate, and isosorbide dimethyl ether; preferably, C 10 ~C 20 The fatty alcohols are selected from one or more of oleyl alcohol, glycerol, lauryl alcohol, and octyldodecyl alcohol. Among them, oleic acid, oleyl alcohol, triacetin, coconut oil ester caprylate, isopropyl palmitate, and dimethyl sulfoxide have better permeation-enhancing effects, good compatibility with cinnamate and pressure-sensitive adhesives, and do not adversely affect the colloidal properties.

[0041] Cinacalcet free base is easily oxidized. This invention reduces the occurrence of oxidation reaction by dispersing cinacalcet free base in a polymer matrix layer. Furthermore, antioxidants can be included in the polymer matrix layer to further improve the product's antioxidant capacity.

[0042] Preferably, the antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, sodium metabisulfite, and ascorbyl palmitate.

[0043] Preferably, the transdermal patch contains 0.3 mg to 2.5 mg of cinacalcet per square centimeter; preferably, the administration area of ​​the transdermal patch is 5 cm². 2 ~100cm 2 .

[0044] Preferably, the transdermal patch of the present invention further comprises a backing layer and a protective layer; the polymer matrix layer is located between the backing layer and the protective layer.

[0045] A second aspect of the present invention provides a method for preparing the transdermal patch described in the first aspect of the present invention, comprising the following steps: (1) Mix the components of the prescription evenly to obtain the adhesive solution; (2) Apply the adhesive obtained in step (1) onto the protective layer and dry it; (3) The product obtained in step (2) is combined with the backing layer and cut to obtain the transdermal patch; Preferably, step (1) involves uniformly mixing cinacalcet free base with a polymer, silicone pressure-sensitive adhesive, and optionally one or more other pharmaceutically acceptable excipients to obtain an adhesive solution; or Step (1) involves first reacting a pharmaceutically acceptable salt of cinacalcet with a basic compound in an organic solvent to generate a cinacalcet free base, then sequentially adding a polymer, a silicone pressure-sensitive adhesive, and one or more other pharmaceutically acceptable excipients, mixing the components evenly to obtain a gel solution; preferably, the organic solvent is ethanol and / or ethyl acetate.

[0046] The third aspect of the present invention provides the use of the transdermal patch described in the first aspect of the present invention in the preparation of a medicament for treating hyperparathyroidism or hypercalcemia; preferably, the use of the transdermal patch in the preparation of a medicament for treating secondary hyperparathyroidism in patients with chronic kidney disease (CKD) undergoing maintenance dialysis or hypercalcemia in patients with parathyroid carcinoma.

[0047] The transdermal patch containing cinacalcet of the present invention offers advantages over oral administration, including convenience, no gastrointestinal irritation or first-pass effect, non-invasiveness, reduced fear of medication, avoidance of fluctuations in blood drug concentration due to oral absorption, and reduced individual differences in bioavailability, significantly increasing patient safety and compliance. The transdermal patch of the present invention exhibits high drug permeability, good adhesion, high safety, no skin irritation, high stability, and good uniformity, meeting the clinical needs for treating hyperparathyroidism or hypercalcemia. Attached Figure Description

[0048] The embodiments of the present invention will now be described in detail with reference to the accompanying drawings, wherein: Figure 1 The figure shows the 12-hour average permeation rate-time curve of the patch in vitro transdermal experiment of Example 7 of the present invention; Figure 2 The blood concentration-time curves of cinacalcet solution administered by gavage and cinacalcet transdermal patch of the present invention to Bama miniature pigs are shown. Detailed Implementation

[0049] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below in conjunction with the accompanying drawings and specific embodiments. It should be understood that these embodiments are only used to illustrate the basic principles, main features, and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to specific requirements. Where specific techniques or conditions are not specified, they are generally performed according to conventional techniques or conditions described in the literature in the art, or according to the product instructions. Unless otherwise specified, the reagents, materials, or instruments used are all conventional products purchased through legitimate commercial channels.

[0050] In the following description, numerous specific details are set forth in order to provide a more thorough understanding of the invention. However, it will be apparent to those skilled in the art that the invention may be practiced without one or more of these details. In other instances, to avoid obscuring the invention, some technical features well-known in the art have not been described; that is, not all features of actual embodiments are described herein, nor are well-known functions and steps described in detail.

[0051] 1. Reagents and their abbreviations

[0052] In the following embodiments, the types, models, and abbreviations of pressure-sensitive adhesives are shown in Table 1.

[0053] Table 1. Types, Models, and Abbreviations of Pressure-Sensitive Adhesives

[0054] For ease of writing, the following embodiments of the present invention use abbreviated numbers to represent the models of each pressure-sensitive adhesive.

[0055] In the following embodiments, the Chinese names represented by the English abbreviations are shown in Table 2.

[0056] Table 2 English Abbreviations

[0057] 2. Preparation method of patch The preparation method of the patch in this embodiment of the invention is as follows: Step 1: Preparation using cinacalcet free base: Weigh the prescribed amounts of each component, stir to mix thoroughly, and obtain a clear gel; or Cinacalcet hydrochloride was prepared by in-situ dissociation: The prescribed amount of cinacalcet hydrochloride was weighed and dissolved in an appropriate amount of ethanol. An equimolar amount of sodium hydroxide ethanol solution was added while stirring. After stirring for a period of time until the reaction was complete, the polymer, pressure-sensitive adhesive, and one or more other pharmaceutically acceptable excipients were added in sequence and stirred to mix evenly to obtain a clear adhesive solution.

[0058] Step 2: The prepared adhesive solution is coated onto a selected release film, with the coating thickness determined according to the application requirements. The coated polymer matrix is ​​then dried. Subsequently, the dried intermediate product is laminated with a selected backing film, cut into appropriate sizes and shapes according to application requirements, and packaged. For ease of comparison, the patches prepared in the following examples all use a coating thickness of 150 μm and a ScotchPak release film. TM 9744 (purchased from 3M), backing film model ScotchPak TM 1109 (purchased from 3M).

[0059] 3. Methods for evaluating the application performance and skin irritation of the patch.

[0060] Take an area of ​​15 cm 2 Rectangular patches were prepared, and after removing the release film, they were applied to the backs of dehaired Bama miniature pigs. The patches were removed after 12 hours, and their adhesion, stringing, delamination, and cold flow were examined and recorded. Patches that were easy to peel off, had suitable adhesion, and exhibited no stringing, delamination, or cold flow (with a black ring around the edge) were considered to have good application performance. Patches exhibiting excessively high or low peel strength, significant stringing, delamination, or cold flow were recorded.

[0061] After removing the patch, observe the skin for any redness, swelling, or other skin irritation issues, and record them.

[0062] 4. Methods for evaluating patch permeability

[0063] In vitro transdermal assay (IVPT): In vitro transdermal assays were performed using a Franz diffusion cell. Skin samples from healthy nude mice were used, and all skin samples were confirmed to be intact before the experiment. A LOGAN SYSTEM 918-12 fully automated transdermal diffusion system was employed. Each sample was tested in triplicate. The receiving solution was a pH 4.5 acetate aqueous solution. The diffusion cell volume was 12 ml, the permeation diameter was 15 mm, the sampling volume was 12 ml, the temperature was 32℃, the system was in full exhaust mode, and the rotation speed was 600 rpm. The procedure was followed, and samples were taken at predetermined time points.

[0064] The cumulative transdermal drug permeation amount and permeation rate (Flux) can be calculated using the following formula:

[0065] In the formula: A 供 =Peak area of ​​the test sample A 对 = Peak area of ​​reference standard C 对 =Concentration of reference standard V 对 =Volume of reference sample injection 供 =Sample injection volume In the following examples, the content of each component is the theoretical dry weight ratio of each component to the polymer matrix layer.

[0066] Example 1: Investigation of the effects of different API forms and pressure-sensitive adhesive types on patches This embodiment investigates the compatibility of cinacalcet free base or its hydrochloride with different pressure-sensitive adhesives and the permeability of the prepared patches. Acrylic pressure-sensitive adhesives (e.g., 2287) and silicone pressure-sensitive adhesives (e.g., 4302) were selected for the study. The state of the adhesive solution after mixing cinacalcet hydrochloride and cinacalcet free base with the adhesive solution was investigated. The application performance and permeability of the prepared patches were also investigated. The results are shown in Tables 3 and 4 below.

[0067] Table 3 Formulations and Colloidal Properties of Different Colloidal Systems

[0068] *The application performance of sample No. 1 was not examined due to crystallization.

[0069] Studies have found that cinacalcet hydrochloride has low solubility in silicone pressure-sensitive adhesives. Patches containing 3% cinacalcet hydrochloride crystallized during storage (approximately 7 days) (Formula No. 1). When preparing silicone pressure-sensitive adhesive patches with a cinacalcet hydrochloride content of 10% (Formula No. 2), the solid cinacalcet hydrochloride could not dissolve in the silicone pressure-sensitive adhesive solution. Further attempts to dissolve the cinacalcet hydrochloride in a polar solvent before adding it to the silicone pressure-sensitive adhesive solution were also made, but this required a large amount of polar solvent, which, upon mixing with the adhesive solution, caused the solution to break down. The concentration of cinacalcet hydrochloride in acrylate pressure-sensitive adhesives is approximately 10%, close to saturation. The solubility of free cinacalcet alkali in pressure-sensitive adhesives is better than that of cinacalcet hydrochloride.

[0070] According to the experimental results in Table 3, in the silicone pressure-sensitive adhesive system, when the content of cinacarpine is 3% (Formula No. 4), the adhesive solution is in good condition after mixing with the adhesive, and the prepared patch has good application performance. However, when the content of cinacarpine is above 5% (Formulas Nos. 5-9), the adhesive solution is destroyed after mixing with the cinacarpine, and solids precipitate out, making it impossible to successfully prepare the patch. The solubility of cinacarpine in acrylate pressure-sensitive adhesives is much greater than its solubility in silicone pressure-sensitive adhesives. In the acrylate pressure-sensitive adhesive system, the colloidal properties are good even when the cinacarpine content is as high as 20%.

[0071] Table 4 IVPT results for different colloidal systems

[0072] As shown in Table 4, the patch prepared from cinacalcet hydrochloride (Formula No. 3) exhibits extremely low drug permeation. The permeation capacity of cinacalcet free base in the silicone pressure-sensitive adhesive system at 3% (Formula No. 4) is higher than that in the acrylate pressure-sensitive adhesive system at 10% and 20% (Formulas Nos. 10 and 11), indicating that silicone pressure-sensitive adhesive has a stronger permeation capacity for cinacalcet than acrylate pressure-sensitive adhesive. However, increasing the cinacalcet content in the silicone pressure-sensitive adhesive system to above 5% leads to adhesive degradation, preventing successful patch preparation. Therefore, conventional methods cannot be used to increase permeation by further increasing the cinacalcet content in the silicone pressure-sensitive adhesive.

[0073] In addition, the stability of the patch was investigated after 0 days, 1 month at room temperature, and 3 months under accelerated conditions (temperature 40℃±2℃, relative humidity 75%±5%). The results are shown in Table 5 below.

[0074] Table 5. Stability test results of different colloidal systems

[0075] *Note: Maximum single impurity limit ≤ 0.5, total impurity limit ≤ 1.

[0076] The patch containing cinacalcet hydrochloride and acrylate pressure-sensitive adhesive (Formula No. 3) had a high impurity content detected 0 days after preparation, and no further stability testing was conducted. The patch containing cinacalcet free alkali and acrylate pressure-sensitive adhesive (Formula No. 11) had a high and rapidly increasing impurity content, indicating a high stability risk. Stability test results showed that cinacalcet's stability in silicone pressure-sensitive adhesive (Formula No. 4) was significantly better than its stability in acrylate pressure-sensitive adhesive. The stability of cinacalcet in the mixture of silicone and acrylate pressure-sensitive adhesives was related to the proportion of acrylate in the mixture. Patches containing a high content of acrylate pressure-sensitive adhesive showed a higher stability risk.

[0077] Example 2: Investigation of the effects of different polymers on the patch Different polymers were added to the cinnamate and silicone pressure-sensitive adhesive system to prepare patches. The state of the adhesive solution and the application performance of the prepared patches were investigated. The experimental results are shown in Table 6 below.

[0078] Table 6. Formulation composition and colloidal properties of different polymers

[0079] The results in Table 6 show that adding a selection of non-water-soluble cellulose derivatives (such as ethyl cellulose), polyvinylpyrrolidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (soluplus) to the silicone pressure-sensitive adhesive system... ® Thickening polymers can effectively improve the compatibility of cinacalcet with silicone pressure-sensitive adhesives and the solubility of cinacalcet in silicone pressure-sensitive adhesive systems, allowing the cinacalcet content in the polymer matrix layer to be increased to at least 10% without causing adhesive degradation, making it suitable for preparing patch products. The addition of non-water-soluble cellulose derivatives (such as ethyl cellulose) is most effective, increasing the cinacalcet content in silicone pressure-sensitive adhesives to 40%, and producing patches with good application performance. However, other thickening polymers, such as eutectic... ® L100, HPMC, polyvinyl alcohol, and CMC-Na failed to effectively improve the solubility of cinacalcet in silicone pressure-sensitive adhesive systems and the problem of adhesive degradation caused by high cinacalcet content, making it impossible to successfully prepare patches. Furthermore, during the preparation of blank (cinacalcet-free) patches, it was found that when ethyl cellulose and silicone pressure-sensitive adhesive were mixed alone, their compatibility was poor, making it impossible to prepare a homogeneous adhesive solution. However, unexpectedly, mixing ethyl cellulose and cinacalcet together into the silicone pressure-sensitive adhesive solved the problems of incompatibility and adhesive degradation caused by cinacalcet.

[0080] Examples 3-12 In the following examples, cinacalcet free base is used as the active pharmaceutical ingredient. The pressure-sensitive adhesive is selected from silicone pressure-sensitive adhesive (e.g., 4301 or 4302) or a mixture of silicone pressure-sensitive adhesive (e.g., 4301 or 4302) and acrylic pressure-sensitive adhesive (e.g., 2287). The polymer is selected from polyvinylpyrrolidone, ethyl cellulose or soluplus, respectively. ® Transdermal patches containing cinacalcet were prepared according to the aforementioned "2. Preparation Method of Patch". The application performance, skin irritation, and permeability of each patch were then examined according to the aforementioned "3. Method for Examining the Application Performance and Skin Irritation of the Patch" and "4. Method for Evaluating the Permeability of the Patch". Specific components, contents, and experimental results are shown in Table 7.

[0081] Table 7. Preparation and performance evaluation of transdermal patches with different compositions

[0082] The results in Table 7 show that, compared with Formulation 4 of Example 1 (without the addition of polymers, Flux value was 3 μg / cm³), 2 Compared to patches with a / h ratio, adding a selection of insoluble cellulose derivatives (such as ethyl cellulose), polyvinylpyrrolidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (soluplus) to the silicone pressure-sensitive adhesive system... ® Patches prepared from high-molecular polymers significantly improved drug permeability while increasing drug content. Among them, patches containing ethyl cellulose exhibited the strongest drug permeability, which gradually increased with increasing drug content in the matrix layer. When the drug content was 25-35%, drug permeability was significantly enhanced, reaching a permeation rate (Flux value) of 15 μg / cm³ after 8 hours. 2 / h or higher. When the drug content is above 30%, further increasing the drug content does not significantly increase the permeability. There are no particular restrictions on the specific type of ethyl cellulose used. Further experiments have confirmed that using ethyl cellulose with different molecular weights and viscosities (e.g., ECN10, ECN50, ECN100, etc.) can significantly improve drug permeability. Furthermore, adding acrylate pressure-sensitive adhesive to the silicone pressure-sensitive adhesive system leads to a significant decrease in drug permeability. Preferably, the weight ratio of the acrylate pressure-sensitive adhesive to the silicone pressure-sensitive adhesive is no greater than 1:1. Particularly preferably, the polymer matrix layer does not contain acrylate pressure-sensitive adhesive.

[0083] Examples 13-21 To further improve permeability, the addition of a permeation enhancer to the silicone adhesive system was investigated. In the following examples, cinacalcet, the active pharmaceutical ingredient, was prepared using an in-situ dissociation method. Cinacalcet was generated by reacting cinacalcet hydrochloride with NaOH in an ethanol solution at a molar ratio of 1:1. The pressure-sensitive adhesive used was silicone pressure-sensitive adhesive (Liveo™ BIO-PSA 7-4302), and the polymer used was ethyl cellulose. The formulation may also include fillers and antioxidants. Transdermal patches containing cinacalcet were prepared according to the aforementioned "2. Preparation Method of Patch," and the application performance, skin irritation, and permeability of each patch were investigated according to the aforementioned "3. Method for Examining the Application Performance and Skin Irritation of the Patch" and "4. Method for Evaluating the Permeability of the Patch." Specific components, contents, and experimental results are shown in Table 8.

[0084] Table 8. Preparation and performance evaluation of transdermal patches with different compositions.

[0085] *Note: The water generated by in-situ dissociation is removed from the final product after drying.

[0086] As shown in Table 8, the experimental results indicate that adding a penetration enhancer to the system of silicone pressure-sensitive adhesive, cinacalcet, and polymer in this invention can further improve drug permeability. Oleic acid, oleyl alcohol, triacetin, isopropyl palmitate, coconut oil ester caprylate, and dimethyl sulfoxide exhibit good compatibility with cinacalcet, polymer, and silicone pressure-sensitive adhesive, resulting in good penetration enhancement. However, adding a penetration enhancer, especially in large quantities, may lead to a softer, stickier colloid, causing stringing problems. Adding hydrophobic colloidal silica as a filler can further improve the adhesive application performance.

[0087] Experimental Example 1: Stability Study Transdermal patches containing cinakase, silicone pressure-sensitive adhesive (Liveo™ BIO-PSA 7-4301), ethyl cellulose, and optional antioxidants were prepared according to the aforementioned “2. Preparation Method of Patch”. The specific components and contents are shown in Table 9 below.

[0088] Table 9 Preparation of transdermal patches with different compositions

[0089] The patch samples of Examples 17 and 22-25 were placed at a temperature of 25℃±2℃ and a relative humidity of 60%±5% for 6 months to examine the long-term stability of the patches. The results are listed in Table 10 below.

[0090] Table 10 Results of Long-Term Stability Tests

[0091] As can be seen from the results in Table 10, the impurity content of the patches of the present invention met the limit requirements during the long-term stability test, indicating that the patches of the present invention have good stability. The stability of the patches prepared by the in-situ dissociation method is better than that of the patches prepared using cinacalcet free base, especially with significantly lower impurity content at day 0. Furthermore, the stability of the patch samples with added tocopherol or BHT as antioxidants is significantly better than that of the patch samples with added L-AP as antioxidants.

[0092] Experimental Example 2: Content Uniformity Detection Drug content was sampled and tested from different patch samples 1 to 10 of the same batch of patches prepared according to the prescription of Example 20 to examine the uniformity of patch content. The experimental results are shown in Table 11 below: Table 11 Results of Content Uniformity Test for Patch Samples

[0093] The results in Table 11 show that the uniformity of patch content meets the requirements, indicating that the product has good uniformity.

[0094] Experimental Example 3: Pharmacokinetic Experiment of Bama Miniature Pigs 1. Drug Information Cinacalcet hydrochloride raw material: Batch number: 230201, Specification: 300g / bag, Manufacturer: Zhejiang Guobang Pharmaceutical Co., Ltd.

[0095] Cinacalcet transdermal patch: Cinacalcet patch of Example 20 of this invention; cut specifications: 4cm × 5cm, application area 20cm² 2 .

[0096] 2. Laboratory animals Three healthy Bama miniature pigs, male, 30 days old, weighing 2.5~3.5kg.

[0097] 3. Dosing regimen Bama miniature pigs were divided into a Sinacalse gavage group and a Sinacalse transdermal patch group.

[0098] The cinacase gavage group was given a single oral gavage of 1 mg / kg of cinacase solution to Bama miniature pigs.

[0099] The administration regimen for cinacalcet via gavage is shown in the table below:

[0100] The dosing regimen for the cinacalcet transdermal patch is shown in the table below:

[0101] Hair was removed from the application site on the animals before application. The backing film was peeled off using a disposable tube, and the adhesive side of the backing film was applied to the pre-treated skin, gently pressing and spreading it 2-3 times. After 24 hours of continuous application, drug administration was stopped, the patches were removed, and placed in wide-mouth bottles for subsequent analysis.

[0102] 4. Sample Collection Whole blood samples were collected from the cinacalcet gavage group at 0h, 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, and 36h after gavage administration. Whole blood samples were collected from the cinacalcet transdermal patch group at 0h, 4h, 8h, 10h, 12h, 16h, 24h (after administration was stopped), 25h, 26h, 28h, 32h, and 48h after patch administration. Approximately 0.4 mL of whole blood was collected at each time point and placed in blood collection tubes containing EDTA-K2. The whole blood was centrifuged at 2-8 ℃, 2000 g, and 10 min within 1 hour of collection. Plasma was then collected into new EP tubes with a volume of not less than 200 µL and placed in an ultra-low temperature freezer. After the experiment, the plasma samples were transferred to the biological laboratory and frozen in an ultra-low temperature freezer.

[0103] Sample collection follows the relevant SOP (Standard Operating Procedure).

[0104] 5. Biological sample analysis The collected samples were tested using a feasibility-verified LC-MS / MS sample detection method.

[0105] The drug concentration in the residual patch was determined using a feasibility-verified HPLC method.

[0106] 6. Data Statistics The experimental data were statistically analyzed using WinNonlin software, and pharmacokinetic parameters were calculated. The results are shown in [Figure number missing]. Figure 2 .

[0107] 7. Results The results showed that applying a 20cm transdermal patch of cinakasec to miniature pigs in Bama was effective. 2 (24h) The blood drug concentration is comparable to that of 1 mg / kg (human equivalent dose) administered by gavage, and can maintain a stable blood drug concentration for a longer period of time. The transdermal drug delivery formulation of the present invention can avoid the first-pass effect of the liver and the adverse reactions caused by oral administration. At the same time, compared with oral administration, the blood drug concentration is more stable and sustained, and has higher bioavailability, showing significant efficacy in the treatment of hyperthyroidism.

[0108] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A transdermal patch containing cinacalcet, comprising a polymer matrix layer, said polymer matrix layer comprising cinacalcet, silicone pressure-sensitive adhesive, and one or more polymers selected from water-insoluble cellulose derivatives, polyvinylpyrrolidone, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers.

2. The transdermal patch according to claim 1, wherein the polymer is a non-water-soluble cellulose derivative; Preferably, the weight content of the cinakaser is 10% to 40%, the weight content of the polymer is 3% to 15%, and the weight content of the silicone pressure-sensitive adhesive is 30% to 80%, based on the weight of the polymer matrix layer.

3. The transdermal patch according to claim 1 or 2, wherein the cinacalcet is generated by in-situ dissociation reaction of a pharmaceutically acceptable salt of cinacalcet with a basic compound; Preferably, the pharmaceutically acceptable salt of cinacalcet is selected from cinacalcet inorganic acid salts or cinacalcet organic acid salts, and more preferably one or more of cinacalcet hydrochloride, cinacalcet hydrobromide, cinacalcet sulfate, cinacalcet nitrate, cinacalcet phosphate, cinacalcet methanesulfonate, cinacalcet succinate, cinacalcet acetate, and cinacalcet ascorbate. Preferably, the alkaline compound is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, and sodium carbonate.

4. The transdermal patch according to any one of claims 1 to 3, wherein the silicone pressure-sensitive adhesive is selected from one or more of Liveo™ BIO-PSA 7-4101, Liveo™ BIO-PSA 7-4102, Liveo™ BIO-PSA 7-4201, Liveo™ BIO-PSA 7-4202, Liveo™ BIO-PSA 7-4301, Liveo™ BIO-PSA 7-4302, Liveo™ BIO-PSA 7-4401, Liveo™ BIO-PSA 7-4402, Liveo™ BIO-PSA 7-4501, Liveo™ BIO-PSA 7-4502, Liveo™ BIO-PSA 7-4601, and Liveo™ BIO-PSA 7-4602; The insoluble cellulose derivative is selected from one or more of ethyl cellulose, cellulose acetate, and cellulose acetate butyrate; preferably, the viscosity of the ethyl cellulose is 5-300 cps; preferably, the weight-average molecular weight of the ethyl cellulose is 20,000-300,000; and / or The polyvinylpyrrolidone is selected from one or more of PVP K30 and PVP K90.

5. The transdermal patch according to any one of claims 1 to 4, wherein the polymer matrix layer further comprises an acrylate pressure-sensitive adhesive; preferably, the weight ratio of the acrylate pressure-sensitive adhesive to the silicone pressure-sensitive adhesive is not greater than 1:1, more preferably, the weight ratio of the acrylate pressure-sensitive adhesive to the silicone pressure-sensitive adhesive is not greater than 2:3, and even more preferably, the weight ratio of the acrylate pressure-sensitive adhesive to the silicone pressure-sensitive adhesive is not greater than 1:5; Particularly preferably, the polymer matrix layer does not contain acrylate pressure-sensitive adhesive.

6. The transdermal patch according to any one of claims 1 to 5, wherein the polymer matrix layer further comprises one or more other pharmaceutically acceptable excipients. Preferably, the other pharmaceutically acceptable excipients are one or more of fillers, penetration enhancers, and antioxidants. Preferably, based on the weight of the polymer matrix layer, the filler content is 0.5% to 15%, more preferably 2% to 12%, and even more preferably 5% to 11%; the penetration enhancer content is 0.1% to 20%, more preferably 0.5% to 15%, and even more preferably 1% to 12%; and / or the antioxidant content is 0.01% to 1%, more preferably 0.1% to 0.8%, and even more preferably 0.4% to 0.6%; Preferably, the filler is selected from one or more of talc, bentonite, kaolin, hydrophobic colloidal silica, and montmorillonite; Preferably, the penetration enhancer is selected from one or more of fatty alcohols, fatty alcohol amines, fatty acids, fatty acid esters, fatty ethers, dimethyl sulfoxide, and azone; preferably, the penetration enhancer is selected from C 10 ~C 20 One or more of the following: fatty alcohols, triethanolamine, oleic acid, coconut oil ester caprylate, isopropyl palmitate, isopropyl myristate, cocoyl caprylate caprylate, ethyl oleate, triethyl citrate, glyceryl monooleate, glyceryl triacetate, and isosorbide dimethyl ether; preferably, C 10 ~C 20 Fatty alcohols are selected from one or more of oleyl alcohol, glycerol, lauryl alcohol, and octyldodecyl alcohol; Preferably, the antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, sodium metabisulfite, and ascorbyl palmitate.

7. The transdermal patch according to any one of claims 1 to 6, wherein the amount of cinacalcet contained in the transdermal patch is 0.3 mg to 2.5 mg per square centimeter; preferably, the administration area of ​​the transdermal patch is 5 cm². 2 ~100cm 2 .

8. The transdermal patch according to any one of claims 1 to 7, further comprising a backing layer and a protective layer; wherein the polymer matrix layer is located between the backing layer and the protective layer.

9. A method for preparing the transdermal patch according to any one of claims 1 to 8, comprising the following steps: (1) Mix the components of the prescription evenly to obtain the adhesive solution; (2) Apply the adhesive obtained in step (1) onto the protective layer and dry it; (3) The product obtained in step (2) is combined with the backing layer and cut to obtain the transdermal patch; Preferably, step (1) involves uniformly mixing cinacalcet free base with a polymer, silicone pressure-sensitive adhesive, and optionally one or more other pharmaceutically acceptable excipients to obtain an adhesive solution; or Step (1) involves first reacting a pharmaceutically acceptable salt of cinacalcet with a basic compound in an organic solvent to generate a cinacalcet free base, then sequentially adding a polymer, a silicone pressure-sensitive adhesive, and one or more other pharmaceutically acceptable excipients, mixing the components evenly to obtain a gel solution; preferably, the organic solvent is ethanol and / or ethyl acetate.

10. Use of the transdermal patch according to any one of claims 1 to 8 in the preparation of a medicament for treating hyperparathyroidism or hypercalcemia; preferably, use of the transdermal patch in the preparation of a medicament for treating secondary hyperparathyroidism in patients undergoing maintenance dialysis for chronic kidney disease or hypercalcemia in patients with parathyroid carcinoma.

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