Colchicine-containing patch as well as preparation method and application thereof

Abstract

The invention relates to a colchicine-containing patch as well as a preparation method and application thereof, the patch comprises a polymer matrix layer, and the polymer matrix layer comprises the following components in percentage by weight: 0.1-5.0% of colchicine, 0.1-5.0% of chitosan, 0.1-5.0% of chitosan and the balance of water. 0.005%-15% of a penetration enhancer; and 80%-99% of a pressure-sensitive adhesive. The colchicine-containing patch provided by the invention can achieve a treatment effect through percutaneous penetration, has no local irritation during application and after application, has no gastrointestinal side effects, and has high patient compliance.

Description

[0001] This application is a divisional application of Chinese invention patent application filed on September 28, 2023, with application number 202311272846.6 and entitled "Patch Containing Colchicine and its Preparation Method and Application".

[0002] This invention claims priority to the following patent application: Chinese patent application filed on September 30, 2022, with application number 202211213655.8, entitled "Colchicine-containing patch and its preparation method and application", the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of transdermal drug delivery technology, specifically relating to a patch containing colchicine, its preparation method, and its application. Background Technology

[0004] Colchicine, chemically known as N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[α]cycloheptatrien-7-yl)-(S)-acetamide, has the molecular formula C2. 22 H 25 NO6, with a molecular weight of 399.4, is a pale yellow to pale yellow-green amorphous or crystalline powder, odorless, and darkens in color upon exposure to light. Its chemical structure is as follows:

[0005] Colchicine has a unique tricyclic structure and is unstable under high temperature and light conditions, especially producing genotoxic impurities C and G under light. The chemical structures of impurities C and G are as follows:

[0006] Colchicine, a natural plant alkaloid, has been used by humans since before Christ, and its pure form was first extracted from the autumn crocus plant in 1820. Currently, colchicine is approved by major drug regulatory agencies such as the FDA, PDMA, EMA, and NPMA for the prevention and treatment of gout. Gout has become the second leading metabolic disease after diabetes, and colchicine is currently a first-line treatment and preventative drug for acute gout attacks. Besides gout, colchicine is also used to treat other diseases, such as Mediterranean fever, cardiovascular diseases like pericarditis, skin diseases like Sweet's syndrome, and psoriasis.

[0007] However, colchicine has a small therapeutic safety window due to the close proximity of its therapeutic and toxic doses; it also has low bioavailability due to its first-pass effect in the liver. Currently approved oral colchicine formulations all have serious side effects, such as abdominal pain, nausea, vomiting, diarrhea, bone marrow suppression, arrhythmia, and azoospermia. Therefore, despite its high clinical efficacy, these severe side effects prevent more than 80% of patients from adhering to oral colchicine treatment.

[0008] Transdermal drug delivery system (TDDS) refers to a drug delivery method in which the drug is absorbed through the skin or mucous membranes and exerts its pharmaceutical effect at the local treatment site or systemically. Transdermal delivery offers many advantages, such as no gastrointestinal irritation, avoidance of the first-pass effect of the liver, non-invasiveness, long-lasting release, reduced frequency of dosing, and avoidance of fluctuations in blood drug concentration caused by oral absorption, thus resulting in higher safety and better patient compliance.

[0009] However, although some attempts to deliver colchicine via transdermal administration have been reported in the literature, the clinical need for higher safety and better compliance with colchicine has not yet been met. Therefore, there is an urgent need for a transdermal drug delivery system that can safely and effectively deliver colchicine. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide a colchicine-containing patch, its preparation method and application, wherein the patch includes a polymer matrix layer, and the polymer matrix layer contains the following components by weight percentage: colchicine 0.1%~5.0%; penetration enhancer 0.005%~15%; pressure-sensitive adhesive 80%~99%. The colchicine-containing patch of the present invention can achieve a therapeutic effect through transdermal penetration, has no local irritation during and after application, no gastrointestinal side effects, and has high patient compliance.

[0011] To solve the above technical problems, the technical solution adopted by the present invention is as follows: A patch containing colchicine includes a polymer matrix layer, wherein the polymer matrix layer comprises, by weight percentage, the following components: Colchicine 0.1%~5.0% Penetration enhancer 0.005%~15% Pressure-sensitive adhesive 80%~99%.

[0012] Preferably, the weight percentage of colchicine in the polymer matrix layer is 0.25% to 4.0%, more preferably 0.50% to 3.5%, even more preferably 0.50% to 3.0%, and more specifically 0.50%, 1.0%, 1.5%, 2.0%, 2.5%, and 3.0%.

[0013] Preferably, the weight percentage of the penetration enhancer in the polymer matrix layer is 0.01% to 12%, specifically 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.50%, 0.70%, 1.00%, 1.50%, 2.00%, 3.00%, 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, and 10.00%.

[0014] Preferably, the weight percentage of pressure-sensitive adhesive in the polymer matrix layer is 85% to 98%, specifically 85%, 90%, 95%, or 98%.

[0015] Preferably, the patch containing colchicine also includes a backing layer; Preferably, the patch containing colchicine also includes a protective layer, with a polymer matrix layer located between the backing layer and the protective layer.

[0016] Preferably, the penetration enhancer is selected from reagents that can dissolve colchicine and have a boiling point greater than or equal to 150°C; Preferably, the penetration enhancer is selected from one or more of alcohols, alkanolamines, and alcohol ethers; Preferably, the boiling point of the penetration enhancer is greater than or equal to 180°C; Preferably, the alcohols are selected from monohydric alcohols and / or dihydric alcohols; Preferably, the monohydric alcohol is selected from one or more of lauryl alcohol, oleyl alcohol, and terpineol; Preferably, the diol is selected from self-diol; Preferably, the alkanolamine is selected from one or more of tromethamine, ethanolamine, diethanolamine, triethanolamine, N-hydroxyethylpiperidine, N-hydroxyethylpyrrolidine, N-hydroxyethylpiperazine, N,N-dibutylaminoethanol and N,N-diethylaminoethanol; Preferably, the alcohol ether is selected from one or more of diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monohexyl ether, dipropylene glycol methyl ether, dipropylene glycol butyl ether, and dipropylene glycol condensate.

[0017] Preferably, the backing layer is selected from closed backing films or non-closed backing films; Preferably, the backing layer is selected from closed backing films; Preferably, the closed backing film is selected from light-shielding closed backing films; Preferably, the closed backing film is selected from a polyester-polyethylene composite film with a metal aluminum liner; Preferably, the thickness of the closed backing film is 20~100μm.

[0018] Preferably, the protective layer is selected from release film.

[0019] Preferably, the pressure-sensitive adhesive is selected from one or a mixture of two of acrylic pressure-sensitive adhesives or polysilicon pressure-sensitive adhesives.

[0020] More preferably, the pressure-sensitive adhesive is one or more of Liveo™ BIO-PSA 7-4302, Liveo™ 7-6302 SilicaHybrid PSA, and DURO-TAK 87-900A.

[0021] Preferably, the colchicine content in the polymer matrix layer is in the range of 10 μg / cm³. 2 ~150μg / cm 2 ; Preferably, the application area of ​​the patch containing colchicine is 5 cm². 2 ~100cm 2 .

[0022] To solve the above technical problems, another technical solution adopted by the present invention is: A method for preparing a patch containing colchicine as described above includes the following steps: (1) Dissolve the prescribed amount of colchicine and penetration enhancer in an organic solvent to obtain a mixture; (2) Add the mixture obtained in step (1) to the prescribed amount of pressure-sensitive adhesive to obtain the adhesive solution; (3) Apply the adhesive obtained in step (2) onto the protective layer and remove the organic solvent; (4) The product obtained in step (3) is combined with the backing layer and punched to obtain a patch containing colchicine.

[0023] To solve the above technical problems, another technical solution adopted by the present invention is: A method for preparing a patch containing colchicine as described above includes the following steps: (1) Add the prescribed amounts of colchicine, penetration enhancer and pressure-sensitive adhesive to an organic solvent and mix to obtain an adhesive solution; (2) Apply the adhesive obtained in step (1) onto the protective layer and remove the organic solvent; (3) The product obtained in step (2) is combined with the backing layer and punched to obtain a patch containing colchicine.

[0024] Preferably, the organic solvent in step (1) is selected from one or more of methanol, ethanol, or isopropanol; Preferably, the specific operation for removing organic solvents is as follows: drying at 35~50℃ to remove organic solvents.

[0025] To solve the above technical problems, another technical solution adopted by the present invention is: The use of a colchicine-containing patch as described above in the preparation of a medicament for the prevention and / or treatment of gout and / or pericarditis.

[0026] Due to the adoption of the above technical solutions, the present invention has the following advantages compared with the prior art: 1. The colchicine-containing patch of the present invention contains a colchicine content that can achieve a therapeutic effect through transdermal penetration, while not causing local skin irritation or gastrointestinal side effects during and after application, resulting in high patient compliance. 2. The permeation enhancer of this invention can promote the continuous and controllable transdermal permeation of colchicine to achieve the therapeutic effect, and has good compatibility with colloidal matrix; 3. The colchicine-containing patch of the present invention includes a backing layer that is directly connected to the polymer matrix layer. During use, the backing layer protects the polymer matrix layer from contact with the surrounding environment and prevents drug loss. 4. The backing layer of the present invention is preferably a closed light-shielding backing film. The closed backing film has good controllable permeability and the colloidal matrix remains in a good state after application, thereby maintaining good adhesion performance and meeting the wearing requirements during the use of the patch. The light-shielding backing film reduces or eliminates the risk of colchicine decomposition upon exposure to light. Attached Figure Description

[0027] Figure 1a The state diagrams of colchicine dissolved in 4098 pressure-sensitive adhesive at day 0 are shown. Figure 1b The images show the state of different amounts of colchicine in 4098 pressure-sensitive adhesive after being left at room temperature for 4 months. Figure 2 This is a graph showing the in vitro permeation test results of the patch in Example 24; Figure 3 This is a diagram showing the results of the in vivo permeation test of the patch in Example 24; Figure 4 The plasma concentrations in various tissues of male Bama miniature pigs after a single transdermal administration of 11.9 mg / pig of colchicine patch in Experiment Example 7 were determined. Figure 5 and Figure 6 They are respectively Figure 4 A magnified view of a portion of the image; Figure 7 The plasma concentrations in various tissues of male Bama miniature pigs after a single gavage administration of 1 mg / pig of colchicine tablets in Experiment Example 7 were measured. Detailed Implementation

[0028] Specifically, this invention provides a patch containing colchicine, comprising a polymer matrix layer, wherein the polymer matrix layer contains the following components by weight percentage: Colchicine 0.1%~5.0% Penetration enhancer 0.005%~15% Pressure-sensitive adhesive 80%~99%.

[0029] Colchicine has a certain degree of skin irritation. This irritation is related not only to the composition of the colloidal matrix, including but not limited to the type and content of the penetration enhancer and the type and composition of the pressure-sensitive adhesive, but also directly to the content of colchicine. Therefore, in order to reduce or eliminate local skin irritation at the application site of the colchicine-containing patch while ensuring the therapeutic dose is delivered, in some specific embodiments, the weight of colchicine as a percentage of the dry weight of the polymer matrix layer is 0.1% to 5.0%, preferably 0.25% to 4.0%, more preferably 0.50% to 3.5%, more preferably 0.50% to 3.0%, and more specifically 0.50%, 1.0%, 1.5%, 2.0%, 2.5%, and 3.0%. At the above content, it is possible to ensure that the colchicine-containing patch continuously and controllably delivers the amount required to achieve the therapeutic effect during the application period while reducing or eliminating local skin irritation.

[0030] To achieve the therapeutic effect through transdermal penetration, this invention contains a penetration enhancer. However, not all types of penetration enhancers can achieve the purpose of this invention. This is because colchicine's unique structure results in excellent water solubility; it is generally readily soluble in alcohols and their derivatives, but poorly soluble in less polar solvents such as ethyl acetate. The pressure-sensitive adhesive system used in this invention primarily uses ethyl acetate as the solvent. Therefore, one problem this invention aims to solve is selecting a suitable penetration enhancer to promote the transdermal penetration of colchicine to achieve the therapeutic dose, while simultaneously ensuring that colchicine is uniformly dissolved or dispersed in a colloidal matrix containing ethyl acetate as the main solvent.

[0031] In some specific embodiments, the penetration enhancer includes, but is not limited to, alcohols such as methanol, ethanol, diethanol, terpineol, oleyl alcohol, camphor, borneol, etc., alcohol ethers such as diethylene glycol monomethyl ether, alcohol amines such as triethanolamine, N-hydroxyethylpyrrolidone, etc., and others such as dimethyl sulfoxide (DMSO), N-methylpyrrolidone and oleic acid, etc.

[0032] This invention unexpectedly discovered that in transdermal drug delivery systems, some penetration enhancers, while enhancing penetration, may potentially damage the colloidal properties of pressure-sensitive adhesives, especially at higher concentrations. For example, in some specific embodiments, the addition of certain penetration enhancers causes the pressure-sensitive adhesive in solution to partially transform into a gel state or partially form lumps, thereby altering the colloidal rheology and further leading to coating failure. In some specific embodiments, increasing the concentration of the penetration enhancer further degrades the colloidal properties. Therefore, this invention selects penetration enhancers while simultaneously considering both the penetration-enhancing effect and the colloidal properties. This invention also found that certain types of penetration enhancers have good compatibility with the colloidal matrix and can achieve the desired effect of increasing the diffusion rate.

[0033] In some specific embodiments, the penetration enhancer is selected from reagents that can dissolve colchicine and have a boiling point greater than or equal to 150°C.

[0034] In some specific embodiments, the penetration enhancer is selected from one or more of alcohols, alkanolamines, and alcohol ethers.

[0035] In some specific embodiments, the boiling point of the penetration enhancer is greater than or equal to 180°C.

[0036] In some specific embodiments, the alcohols are selected from monohydric alcohols and / or dihydric alcohols.

[0037] In some specific embodiments, monohydric alcohols include, but are not limited to, lauryl alcohol, oleyl alcohol, and terpineol; dihydric alcohols include, but are not limited to, hexanediol; alcoholic amines include, but are not limited to, tromethamine, ethanolamine, diethanolamine, triethanolamine, N-hydroxyethylpiperidine, N-hydroxyethylpyrrolidine, N-hydroxyethylpiperazine, N,N-dibutylaminoethanol, and N,N-diethylaminoethanol; and alcohol ethers include, but are not limited to, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monohexyl ether, dipropylene glycol methyl ether, dipropylene glycol butyl ether, and dipropylene glycol condensate.

[0038] In some specific embodiments, the penetration enhancer may be used alone or in combination.

[0039] Permeation enhancers not only promote the permeation of colchicine, but monohydric alcohols, dihydric alcohols, alkanolamines, or alcohol ethers also increase the solubility of colchicine in colloidal matrices. Therefore, the solubility of colchicine in colloidal matrices tends to increase after the addition of a permeation enhancer. Another implication of increased solubility is that, for the same concentration, colchicine is further from reaching or approaching its maximum saturation solubility. However, the thermodynamic passive diffusion capacity of colchicine is directly related to the degree of approaching saturation solubility; generally, it exhibits the highest thermodynamic passive diffusion capacity when reaching or approaching maximum saturation solubility. Therefore, the addition of solubilizing permeation enhancers increases the solubility of colchicine in the colloidal matrix, thereby reducing its passive thermodynamic diffusion capacity to some extent.

[0040] Therefore, the permeation-enhancing ability is related not only to the type of permeation enhancer but also to its content. Consequently, in some specific embodiments, the addition of a permeation enhancer actually reduces permeation capacity and fails to achieve the desired effect. Although permeation capacity can be increased by further increasing the colchicine content to reach or approach saturation solubility, a method known in the art, is available. However, the content-dependent local skin irritation of colchicine limits the ability to increase permeation capacity by further increasing the colchicine content in the colloidal matrix to reach or approach saturation solubility.

[0041] In some specific embodiments, the weight of the penetration enhancer accounts for 0.005% to 15% of the dry weight of the polymer matrix layer, preferably 0.01% to 12%, and can specifically be 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.50%, 0.70%, 1.00%, 1.50%, 2.00%, 3.00%, 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, and 10.00%.

[0042] The pressure-sensitive adhesive is selected from a pharmaceutically suitable pressure-sensitive adhesive for transdermal drug delivery systems. In some specific embodiments, it is selected from either acrylic pressure-sensitive adhesives based on acrylic polymers or polysilicone pressure-sensitive adhesives based on polysilicone polymers.

[0043] In some specific embodiments, the acrylic pressure-sensitive adhesive can be any homopolymer, copolymer, trimer, or polymer of different acrylic acids. Depending on the functional groups it contains, it can be a non-functionalized acrylic pressure-sensitive adhesive or a functionalized acrylic pressure-sensitive adhesive, including but not limited to those containing hydroxyl, carboxyl, or both hydroxyl and carboxyl groups, amino, and epoxy groups. In some embodiments, the type and amount of acrylic pressure-sensitive adhesive vary depending on the amount of colchicine active ingredient added and the amount required to achieve the therapeutic effect; functionalized acrylic pressure-sensitive adhesives, non-functionalized acrylic pressure-sensitive adhesives, or mixtures of both can be selected.

[0044] In some specific embodiments, the weight of the acrylic pressure-sensitive adhesive accounts for 80% to 99% of the dry weight of the polymer matrix layer, preferably 85% to 98%, and specifically 85%, 90%, 95%, and 98%.

[0045] Commercially available acrylic pressure-sensitive adhesives include Henkel's Duro-Tak products, such as Duro-Tak 87-900A, Duro-Tak 87-9301 (non-crosslinked, vinyl acetate-free acrylic pressure-sensitive adhesive, no functional groups), Duro-Tak 87-4098 (non-crosslinked vinyl acetate-free acrylic pressure-sensitive adhesive, no functional groups), Duro-Tak 87-2287 (non-crosslinked vinyl acetate-free acrylic pressure-sensitive adhesive, with hydroxyl functional groups), Duro-Tak 87-2852 (crosslinked acrylic pressure-sensitive adhesive, with carboxyl functional groups), Duro-Tak 87-2196 (crosslinked acrylic pressure-sensitive adhesive, with carboxyl functional groups), and Duro-Tak 87-2296 (crosslinked acrylic pressure-sensitive adhesive, with carboxyl functional groups). Duro-Tak 87-2194 (crosslinked acrylic pressure-sensitive adhesive with carboxyl functional groups), Duro-Tak 87-2516 (crosslinked acrylic pressure-sensitive adhesive with carboxyl functional groups), Duro-Tak 87-2070 (crosslinked acrylic pressure-sensitive adhesive with carboxyl functional groups), Duro-Tak 87-2353 (non-crosslinked acrylic pressure-sensitive adhesive with carboxyl functional groups), Duro-Tak 87-2154 (crosslinked acrylic pressure-sensitive adhesive with carboxyl functional groups), and Duro-Tak 87-2510 (non-crosslinked acrylic pressure-sensitive adhesive with hydroxyl functional groups).

[0046] In some specific embodiments, the weight of the polysilicon pressure-sensitive adhesive accounts for 90% to 99% of the dry weight of the polymer matrix layer, preferably 95% to 99%, and can specifically be 95%, 96%, 97%, 98%, or 99%.

[0047] Commercially available polysiloxane pressure-sensitive adhesives include products from DuPont, such as Liveo™ 7-6102 SilAc Hybrid PSA, Liveo™ 7-6302 SilAc Hybrid PSA, Liveo™ BIO-PSA 7-4502, Liveo™ BIO-PSA 7-4602, Liveo™ BIO-PSA 7-4302, and Liveo™ BIO-PSA 7-4102.

[0048] Colchicine's physicochemical properties result in high solubility in acrylic pressure-sensitive adhesives (PSAs) but low solubility in silicone PSAs. In some specific embodiments, the PSAs can be selected from a mixture of acrylic and silicone PSAs. When acrylic and silicone PSAs are used in combination, the mixing ratio can be adjusted based on a comprehensive consideration of colchicine permeability and safety. The mixing of acrylic and silicone PSAs can be achieved through physical mixing, i.e., mixing the two PSAs with different properties and stirring to form a uniformly dispersed suspension; or through chemical synthesis to obtain a mixed acrylic and silicone PSAs.

[0049] In some specific embodiments, the pressure-sensitive adhesive composed of acrylic pressure-sensitive adhesive and polysiloxane pressure-sensitive adhesive accounts for 90% to 99% of the dry weight of the polymer matrix layer, preferably 95% to 99%, and specifically 95%, 96%, 97%, 98%, or 99%. The dry weight ratio of acrylic pressure-sensitive adhesive to polysiloxane pressure-sensitive adhesive can be 30 to 70:70 to 30, specifically 50:50, 40:60, 60:40, 30:70, or 70:30.

[0050] In some specific embodiments, the colchicine-containing patch also includes a backing layer and a protective layer, with a polymer matrix layer located between the backing layer and the protective layer.

[0051] The backing layer is directly connected to one surface of the polymer matrix layer. During use, the backing layer protects the polymer matrix layer from contact with the surrounding environment and prevents drug loss.

[0052] The protective layer is selected from the release film and is directly bonded to the other surface of the polymer matrix layer. The release film is removed before application.

[0053] In some specific embodiments, the backing layer is selected from pharmaceutically acceptable backing films, including but not limited to polyester, polyester and vinyl acetate composite films, polyethylene and ethyl acetate composite films, polyurethane, polyester-polyethylene composite films with metal foil such as aluminum foil, nonwoven fabrics, elastic fabrics, etc.

[0054] Because colchicine has good water solubility, during the application period, moisture from the skin at the application site enters the colloidal matrix, which affects the solubility of this water-soluble component in the colloidal matrix. This, in turn, affects its thermodynamic diffusion capacity, i.e., permeability and adhesion performance. The degree of influence depends on the application time and the properties of the backing film.

[0055] Therefore, in order to address the impact of moisture generated by skin respiration during application on the permeability and application performance of the patch, in some specific embodiments, the backing layer is selected from closed backing film or non-closed backing film.

[0056] Closed-backed films and non-closed-backed films are classified according to their permeability to moisture and oxygen. Non-closed-backed films allow a certain degree of permeability to oxygen and moisture from skin respiration; for example, non-woven fabrics and elastic fabrics have relatively high permeability to both. Closed-backed films block oxygen and moisture from skin respiration; for example, polyester-polyethylene composite films containing an aluminum liner have extremely low permeability to both moisture and oxygen. The permeability of moisture and oxygen can be adjusted by varying the properties and thickness of the backing film material.

[0057] In some specific embodiments, the backing layer is selected from non-closed backing films. Non-closed backing films facilitate the drainage of moisture and reduce the decrease in the thermodynamic permeability of colchicine, thereby maintaining permeability. However, after a certain period of application, the colloidal matrix of non-closed backing films may partially remain on the skin, leading to peeling failure.

[0058] In some specific embodiments, the backing layer is selected from a closed-back film, which has good controllable permeability and maintains good adhesion performance by keeping the colloidal matrix in a good state after application. The thickness of the closed-back film is 20~100μm, preferably 20~80μm.

[0059] In some specific embodiments, the closing backing film is selected from a polyester-polyethylene composite film with a metal aluminum liner, and the thickness is 20~100μm, preferably 20~80μm.

[0060] In some specific embodiments, the backing film is selected from ScotchPak of 3M. TM 1109, ScotchPak TM 9738 or ScotchPak TM 9730, preferably ScotchPak TM 9738.

[0061] In some specific embodiments, the colchicine content in the polymer matrix layer ranges from 10 μg / cm³. 2 ~150μg / cm 2 It can also be some other ranges, specifically: 15 μg / cm 2 ~120μg / cm 2 20μg / cm 2 ~100μg / cm 2 20μg / cm 2 ~25μg / cm 2 30μg / cm 2 ~35μg / cm 2 More specifically, the range can be 20 μg / cm 2 25μg / cm2 30μg / cm 2 35μg / cm 2 40μg / cm 2 45μg / cm 2 50μg / cm 2 55μg / cm 2 60μg / cm 2 65μg / cm 2 70μg / cm 2 75μg / cm 2 80μg / cm 2 85μg / cm 2 90μg / cm 2 100μg / cm 2 .

[0062] In some specific embodiments, the application area of ​​the colchicine-containing patch is 5 cm², depending on the desired blood drug concentration or clinical effect to be achieved within the application time range. 2 ~100cm 2 It can also be some other ranges, specifically: 10cm 2 ~90cm 2 More specifically, the range can be 10cm. 2 15cm 2 20cm 2 30cm 2 40cm 2 50cm 2 60cm 2 70cm 2 80cm 2 .

[0063] In some specific embodiments, a method for preparing a colchicine-containing patch as described above includes the following steps: (1) Dissolve the prescribed amount of colchicine and penetration enhancer in an organic solvent to obtain a mixture, wherein the weight ratio of colchicine to organic solvent is 1:1; (2) After stirring the mixture obtained in step (1) evenly, add it dropwise to the prescribed amount of pressure-sensitive adhesive at room temperature and at an appropriate rate to obtain the adhesive solution; (3) After stirring the adhesive solution obtained in step (2) evenly, apply it to the protective layer (release film), and dry the coated polymer matrix layer at a certain temperature to remove the organic solvent; (4) The product obtained in step (3) is combined with the backing layer and cut into the required specifications to obtain a patch containing colchicine.

[0064] In some specific embodiments, a method for preparing a colchicine-containing patch as described above includes the following steps: (1) Add the prescribed amounts of colchicine, penetration enhancer and pressure-sensitive adhesive to an organic solvent and mix to obtain an adhesive solution; (2) After stirring the adhesive solution obtained in step (1) evenly, apply it to the protective layer (release film), and dry the coated polymer matrix layer at a certain temperature to remove the organic solvent; (3) The product obtained in step (2) is combined with the backing layer and cut into the required specifications to obtain a patch containing colchicine.

[0065] In some specific embodiments, the organic solvent in step (1) is selected from one or more of methanol, ethanol or isopropanol, preferably ethanol.

[0066] In some specific embodiments, the specific operation for removing organic solvents is as follows: the coated polymer matrix layer is dried at 35~50°C to remove the organic solvents.

[0067] It should be noted that the order of preparation of the patch, the amount of each component added, the stirring time and speed, and other parameters will vary depending on the intended use. These parameters can be adjusted as needed.

[0068] An exemplary preparation method is as follows: Step 1): First, weigh out the prescribed amount of colchicine and penetration enhancer and dissolve them in an appropriate amount of ethanol. Dissolve them while stirring. Depending on the amount added, the stirring time is 15-60 minutes to obtain a mixture. Step 2): While stirring, add the mixture obtained in Step 1) dropwise to the prescribed amount of pressure-sensitive adhesive, and continue stirring for 10-60 minutes to obtain the adhesive solution; Step 3): After thoroughly mixing the adhesive obtained in Step 2), apply it to the release film. The coating thickness is determined according to the final clinical application requirements. Then, dry the film in an oven with exhaust ventilation at 35-50°C. o Dry at C for 5-15 minutes to remove organic solvents. The specific drying temperature and time depend on the coating speed and the amount of residual solvent. Step 4): Combine the product obtained in Step 3) with the selected backing film, and cut it into the required specifications according to the usage requirements to obtain a patch containing colchicine.

[0069] Based on the general preparation method of patches, other methods reported in the literature can also be used to prepare the patches of this invention.

[0070] In some specific embodiments, the patch of the present invention is used in the preparation of medicaments for the prevention and / or treatment of gout and / or pericarditis.

[0071] Terminology Explanation: 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, and where appropriate, terms used in the singular will also include the plural forms, and vice versa.

[0072] The terms "transdermal drug delivery" or "transdermal drug delivery" as used in this invention refer to a method of drug delivery in which an active ingredient is delivered to a local or systemic system through the skin or mucous membrane. These terms have the same meaning in this patent and are interchangeable.

[0073] The terms "polymer matrix layer" or "colloidal matrix layer" used in this invention refer to the material combination of polymeric pressure-sensitive adhesive, colchicine, and other pharmaceutically acceptable excipients included in a transdermal drug delivery system. Generally, 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. In this invention, "polymer matrix layer" and "colloidal matrix layer" have the same meaning and are interchangeable.

[0074] 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 film, and a polymer matrix drug delivery layer located between the two layers. Based on the combination of the active ingredients and other components in the polymer matrix drug delivery 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 interchangeable in this invention. The polymer matrix drug delivery layer generally contains active ingredients, penetration enhancers, and / or other pharmaceutical excipients suitable for transdermal drug delivery patches, including but not limited to pressure-sensitive adhesives, fillers, crosslinking agents, antioxidants, ultraviolet absorbers, antibacterial agents, etc.

[0075] 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 / hr.

[0076] 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 them with only a light pressure and maintain long-term adhesion. Pressure-sensitive adhesives generally include two types: one is inherently pressure-sensitive, while the other can achieve pressure-sensitive adhesive functions by adding tackifiers or plasticizers. 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 application requirements. They generally include acrylic pressure-sensitive adhesives, silicone pressure-sensitive adhesives, and rubber pressure-sensitive adhesives, as well as new hybrid pressure-sensitive adhesives formed by physical mixing or chemical bonding of the above-mentioned pressure-sensitive adhesives, in order to control the properties of the pressure-sensitive adhesive to meet specific requirements.

[0077] The term "backing layer" as used in this invention refers 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. The raw material corresponding to the backing layer is generally called the backing film. Backing layer materials generally include polyester, polyethylene-polyvinyl acetate composite film, polyvinyl chloride, polyurethane, metal foil composite film, non-woven fabric, and elastic fabric, with a thickness generally ranging from 10 to 200 μm. For example, ScotchPak from 3M can be used. TM 9730, 9701, 9720, 9723, Xiaoshan Elastic Fabric 6015A (China), Poring Nonwoven Fabric EW2080, EW2083 (Japan), or Shanghai Winco PE3601. Backing films with different properties have different physicochemical properties, such as extensibility, air permeability, oxygen permeability, and light-blocking properties, thus they can be divided into closed-backing films and non-closed-backing films. In this invention, the backing layer or backing film has the same meaning and can be used interchangeably.

[0078] The term "light-proof closed backing film" used in this invention refers to a type of backing film with extremely low transmittance of moisture, oxygen, and light, and generally contains metal foil of varying thicknesses, such as aluminum foil.

[0079] The term "release film" used in this invention can also be referred to as a protective layer, which is directly connected to the other surface of the polymer matrix layer. The release film is removed before use of the transdermal patch.

[0080] As used in this invention, the terms "through effective dose," "through the amount required to achieve a therapeutic effect," or "effectiveness" refer to the ability of an active ingredient to be delivered 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.

[0081] The term "colchicine" used in this invention refers to a phenolic ketone alkaloid found in the lily family plant *Colchella asiatica*, which can inhibit cell mitosis and thus exert corresponding pharmacological effects.

[0082] The term "penetration enhancer" as used in this invention refers to a substance that can alter the rate at which an active ingredient diffuses into the skin. It is typically miscible with the active ingredient and uniformly dispersed in the polymer matrix layer.

[0083] The term "patch performance" as used in this invention refers to all processes including the peel force (peel force) of the patch detaching from the release film, the peel force (peel force) of the patch detaching from the application site after application, initial tack, holding tack, and cold flow. Specifically: "peel force" refers to the force required to remove the patch from the release film or from the skin after application using the backing layer containing the polymer matrix layer; the peel force should not be too high, as this could lead to peeling failure or adhesive residue on the skin. "Initial tack" refers to the degree of wetting between the backing layer containing the polymer matrix layer and the application site, reducing the risk of detachment during application. "Holding tack" refers to the degree of displacement of the patch at the application site, reflecting the patch strength during application. "Cold flow" refers to the viscoelastic creep of the polymer matrix layer, which can cause the patch to develop a dark ring during wear and may adhere to the protective layer and packaging container during storage, affecting patient safety and effectiveness. Generally, patches need to balance properties such as peel force, initial tack, holding tack, and cold flow.

[0084] The term "colloidal properties" as used in this invention refers to the properties exhibited by the pressure-sensitive adhesive solution after all raw materials and excipients are added to the pressure-sensitive adhesive during the formulation development process, such as changes in rheology and suitability for coating performance.

[0085] As used in this invention, the term "about" indicates a range of ±20% of the following value. In some embodiments, the term "about" indicates a range of ±10% of the following value. In some embodiments, the term "about" indicates a range of ±5% of the following value.

[0086] 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 for illustrative purposes only and are not intended to limit the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are generally performed according to conventional techniques or conditions described in the literature in the art, or according to product instructions. Unless otherwise specified, the reagents, materials, or instruments used are all conventional products that can be purchased through legitimate commercial channels.

[0087] In the following examples and test cases, the pressure-sensitive adhesive models and abbreviations are shown in Table 1.

[0088] Table 1 Pressure-sensitive Adhesive Models and Abbreviations

[0089] In this document, numbers 1 through 11 refer to Henkel polyacrylic pressure-sensitive adhesives. Liveo™ BIO-PSA 7-4302 is a silicone pressure-sensitive adhesive, and Liveo™ 7-6302 SilAc Hybrid PSA is a composite pressure-sensitive adhesive of polyacrylic acid and silicone, commercially sourced from DuPont. For simplicity, the letter parts of each pressure-sensitive adhesive are omitted in the embodiments and test examples of this invention, and only abbreviated numbers are used instead.

[0090] In the following embodiments and test cases, the English abbreviations are shown in Table 2.

[0091] Table 2 English Abbreviations

[0092] This invention relates to a patch containing colchicine, comprising a backing layer, a protective layer, and a polymer matrix layer. The polymer matrix layer contains colchicine, a penetration enhancer, and a pressure-sensitive adhesive, and is located between the backing layer and the protective layer. The backing layer is selected from a light-proof, sealable backing film, the protective layer is selected from a release film, and the penetration enhancer serves to dissolve the active ingredients while also promoting penetration.

[0093] Example 1: Solubility of colchicine active ingredient in different types of pressure-sensitive adhesives Colchicine was dissolved in different concentrations in pressure-sensitive adhesive systems with different properties. The results are shown in Table 3.

[0094] Table 3. Solubility of colchicine active ingredient in different types of pressure-sensitive adhesives

[0095] The results in Table 3 show that colchicine is miscible with different types of polyacrylic pressure-sensitive adhesives and disperses in the colloid to form a homogeneous solution. Colchicine exhibits relatively low solubility / dispersion in polysilicon-based pressure-sensitive adhesive 4302, while for the polyacrylic and polysilicon composite pressure-sensitive adhesive 6302, colchicine shows similar solubility to that in a single polyacrylic pressure-sensitive adhesive. The experimental results indicate that colchicine can achieve certain solubility and dispersion in various polyacrylic, silicone, or mixed acrylic and silicone pressure-sensitive adhesives.

[0096] The stability (whether crystallization) of colchicine with different contents in pressure-sensitive adhesive (taking 4098 pressure-sensitive adhesive as an example) at 0 days and 4 months was observed using an optical magnifying glass. The results are shown in Figure 1.

[0097] Appendix Figure 1aThe images from day zero show that when the colchicine content in the 4098 pressure-sensitive adhesive is 5% or lower, it is transparent; higher contents result in a translucent appearance. (Attached) Figure 1b The images show observations after 4 months. They reveal that when the colchicine content in the 4098 pressure-sensitive adhesive is above 5%, crystals precipitate after 4 months at room temperature. However, when the colchicine content is 5% or lower, no crystals are observed; the adhesive remains transparent and exhibits good adhesion. These stability results indicate that the maximum solubility of colchicine in typical acrylic pressure-sensitive adhesives, without the addition of a penetration enhancer, can reach approximately 5%.

[0098] Examples 2-30 The weight percentages of colchicine, pressure-sensitive adhesive, and penetration enhancer in the polymer matrix layers of Examples 2-30 are shown in Table 4.

[0099] Table 4. Weight percentage of colchicine, pressure-sensitive adhesive, and penetration enhancer in the polymer matrix layer of Examples 2-30

[0100] As shown in Table 4, the addition of different types of permeation enhancers has different effects on permeation efficiency. Non-alcoholic permeation enhancers such as menthol, dimethicone, oleic acid, IPP, PEG600, and DMI did not show significant permeation enhancement effects in either acrylic or silicone pressure-sensitive adhesives. However, alcohols or alcohol derivatives such as DGME, HEP, TEOA, and DPG all showed significant permeation enhancement effects. The permeation enhancement effect is related to the structure of the alcohol. For example, oleyl alcohol and PEG600, although containing hydroxyl groups, did not show any permeation enhancement effect or only a slight effect as the chain length increased.

[0101] Examples 31-44 The components and their weight percentages in the colchicine-containing patches of Examples 31-44 are shown in Table 5.

[0102] Table 5. Components and weight percentages in the colchicine-containing patches of Examples 31-44

[0103] As shown in Table 5, different backing films significantly affect permeability and adhesion performance. 3M Scotchpak™ 9754 (polyester PET), 3M™ CoTran™ 9720 & Shanghai Winco 3601 (polyethylene PE), 3M Scotchpak™ 9733 (polyester PET and polyvinyl acetate EVA hybrid film), Xiaoshan Elastic Fabric 6015A, Japan Baoling Nonwoven Fabric EW2083, and 3M CoTran™ 9701 (polyurethane, PU) all resulted in a significant decrease in permeability. This indicates that non-closed backing films severely affect permeability. A possible reason is that moisture generated by skin respiration at the application site passes through the colloidal matrix layer and then through the backing layer. Due to the excellent water solubility of colchicine, the active ingredients in the colloidal matrix layer dissolve more readily, leading to a decrease in thermodynamic diffusion and consequently a significant reduction in permeability. For completely non-closed backings such as elastic fabric or nonwoven fabric, this further leads to peeling failure. The aluminum-containing closed backing film 3MScotchpak™ 9738 has good permeability, possibly because the closed system prevents moisture from completely passing through the colloidal matrix layer, thus having a smaller impact on the active ingredients and showing no significant change in permeability.

[0104] Comparative Examples 1-12 The weight percentages of colchicine, pressure-sensitive adhesive, and penetration enhancer in the polymer matrix layers of Comparative Examples 1-12 are shown in Table 6.

[0105] Table 6. Weight percentage of colchicine, pressure-sensitive adhesive, and penetration enhancer in the polymer matrix layers of Comparative Examples 1-12

[0106] As can be seen from the results in Table 6, adding short-chain or straight-chain alcohol penetration enhancers will damage the colloidal properties. This is because the short-chain or straight-chain alcohol penetration enhancers have higher polarity, while silicone pressure-sensitive adhesives have very low polarity. Although the penetration enhancer can make colchicine uniformly dissolved or dispersed in the pressure-sensitive adhesive system, the compatibility problem between the penetration enhancer and the pressure-sensitive adhesive causes some of the adhesive solution to change from a uniform solution to a blocky, insoluble, jelly-like mixture, which in turn makes coating impossible.

[0107] Preparation method of Example 2: The preparation method of the patch containing colchicine is as follows: Step 1): First, weigh out the prescribed amounts of colchicine and penetration enhancer, add them to an equal weight of anhydrous ethanol, and stir to dissolve. The stirring time depends on the sample volume, generally 15-30 minutes, to obtain a mixture. Step 2): Weigh the prescribed amount of high molecular weight pressure-sensitive adhesive. While stirring, slowly add the ethanol mixture of colchicine and penetration enhancer obtained in Step 1) to the pressure-sensitive adhesive. The addition time depends on the amount of colchicine ethanol solution, generally 5 to 30 minutes. After the addition is complete, continue stirring for 10 to 30 minutes to ensure that the adhesive matrix is ​​completely and evenly dispersed to obtain the adhesive solution. Step 3): After stirring the adhesive obtained in Step 2) evenly, apply it to the 3M Scotchpak™ 9744 release film. The coating thickness is determined according to the final clinical use requirements. After coating, the polymer matrix is ​​dried in an oven with exhaust function at 35~50℃ for 5~15 minutes to remove organic solvents. The specific drying temperature and time are determined according to the coating speed and the amount of solvent residue. Step 4): The product obtained in Step 3) is laminated with 3M Scotchpak™ 9738 backing film, and finally punched into the required specifications according to the usage requirements, packaged, and a patch containing colchicine is obtained.

[0108] The preparation methods of Examples 3-44 are the same as those of Example 2.

[0109] The preparation methods of Comparative Examples 1-12 are the same as those of Example 2.

[0110] Test Example 1: Colchicine Solubility Test Weigh approximately 2g of colchicine raw material and place it in a 100ml brown volumetric flask. Add 10ml of solvent, mix well, and place in a 25℃ water bath with constant temperature shaker. Observe the solution frequently, and continue adding raw material after the solution becomes clear. After shaking in the 25℃ water bath for 24 hours, if there is still a precipitate in the solution, it indicates that the solution is saturated. Centrifuge the saturated solution and collect the supernatant. Dilute it to a suitable concentration and determine its concentration using the external standard method. Calculate the solubility. The results are shown in Table 7.

[0111] Table 7. Solubility of colchicine in different solvents

[0112] As can be seen from the results in Table 7, colchicine has the highest solubility in water, followed by some solubility in alcohols, alcohol ethers or alcohol amines, and very low solubility in ethyl acetate.

[0113] Test Example 2: Long-term stability test The patch from Example 24 was tested in a long-term stability environment. The test was conducted at 30°C and 60% ± 5% RH. The results are shown in Table 8.

[0114] Table 8. Test results of the patch of Example 24 in a long-term stability environment.

[0115] As can be seen from the results in Table 8, the patch containing colchicine did not produce photodegradation products C and G, or other unknown impurities, during the stability sample storage period, indicating the stability of the transdermal drug delivery system of the present invention.

[0116] Test Example 3: In vitro permeation test The in vitro transdermal assay in Example 24 was performed using a Franz vertical diffusion cell. The back skin of 30-day-old Bama miniature pigs, with a thickness of 0.3 mm, was used. The receiving solution was PBS solution at pH 7.4, the receiving cell volume was 7 mL, the temperature was set at 32 ± 0.1 °C, and the stirring speed was 200 rpm. Samples were taken at 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h, with 3 mL taken each time, followed by the addition of isothermal blank receiving solution. Each sample was tested in triplicate. The cumulative permeation at each time point was calculated as shown in the attached figure. Figure 2 As shown.

[0117] From the appendix Figure 2 The results show that moisture significantly affects the permeation behavior of patches containing colchicine. Due to the high water solubility of colchicine, the permeation capacity decreases significantly after moisture from the receiving medium penetrates into the colloidal matrix of the patch (see Experiment 4, permeation data of Bama miniature pigs on their backs).

[0118] Experimental Example 4: In vivo permeation test of Bama miniature pig Example 24: In vivo permeation test to investigate the effect of moisture on permeation. Test protocol: Samples were pre-placed in a high-humidity environment (92.5% RH) for 72 hours. One sample had a release film, while the other sample had its release film pre-removed to directly expose the colloidal matrix to the high-humidity environment. A live back permeation test was conducted on 30-day-old Bama miniature pigs. The results are attached. Figure 3 As shown.

[0119] From the appendix Figure 3 The results show that moisture significantly affects the permeation behavior of patches containing colchicine. Due to the high water solubility of colchicine, moisture in the environment has a significant impact on permeation behavior; moisture absorbed by the patch from the environment inhibits the permeation behavior of colchicine. After treatment in a high-humidity environment, the in vivo permeation of the sample with the release film on the back of the Bama miniature pig decreased slightly, while the in vivo permeation of the sample without the release film on the back of the Bama miniature pig decreased significantly.

[0120] Experimental Example 5: Local Concentration Test in Rat Joint Capsule Seventy-two male SD rats were randomly divided into six groups according to their body weight, serving as the experimental group and the model control group. The experimental group consisted of low, medium, and high dose groups of test prescription 1, test prescription 2 group, and a colchicine gavage control group. Each experimental and model control group contained 12 rats, and each group was further randomly divided into two subgroups, subgroup 1 and subgroup 2, with 6 rats in each subgroup. Six rats that did not undergo modeling were used as the normal control group. Specific groupings are shown in Table 9. The low, medium, and high dose groups of test prescription 1 correspond to Examples 29, 28, and 24, respectively. The test prescription 2 group corresponds to Example 18.

[0121] Table 9. Grouping of Rats

[0122] Subjects in the low, medium, and high dose groups of test prescription 1 and subject group 2 were administered the medication at 4 and 28 hours after modeling, respectively, and the corresponding test samples (approximately 0.75 cm) were applied to the ankle joint. 2 A 0.5 × 1.5 cm patch was applied to the rats. Simultaneously, the rats' trunks were restrained with gauze and tape, and they were housed individually to prevent them from tearing or biting the patch (if the patch fell off during the experiment, it was recorded and replaced). After 12 hours of continuous application, the patch and trunk restraints were removed. Blank patches were applied to the normal control group and the model control group at the same time and using the same method.

[0123] In the colchicine gavage control group, the colchicine was administered once at 4, 16, 28 and 40 h after modeling, with each dose being 0.25 mg / kg and a volume of 5 mL / kg.

[0124] Subgroups 1 and 2 were dissected at 19 h and 43 h post-modeling, respectively. The normal control group was dissected at 43 h post-modeling. The colchicine concentration in the homogenized joint capsule tissue was measured, and the results are shown in Table 10.

[0125] Table 10. Colchicine concentration in rat joint capsule tissue of each experimental group and control group.

[0126] As can be seen from the results in Table 10, the local colchicine concentration in the joint capsule of rats after patch application was much higher than that after gavage.

[0127] Experimental Example 6: Rabbit Stimulation Test Four Japanese white rabbits were used as a blank control group, a low-dose group of test prescription 1 (Example 29), a medium-dose group of test prescription 1 (Example 28), and a high-dose group of test prescription 1 (Example 24). Four skin sites on the back of each rabbit were treated with the medication. One to two days before administration, the hair at the treatment site was removed using a hair removal device. The area to be treated was approximately a 5*5cm square. Hair removal cream was applied to the treated area, ensuring it was evenly spread. Hair removal took approximately 40-60 seconds. The treated area was then rinsed with warm water to ensure the hair removal cream was completely removed, and the area was patted dry with gauze.

[0128] Before administration, photographs were taken of the skin at the hair removal site. A 3cm diameter test sample was applied to the treatment site and removed after 8 hours. Skin reactions were visually observed at 60 minutes, 24, 48, and 72 hours after removal of the test sample, and the degree of irritation and edema were scored according to Table 11.

[0129] Table 11 Skin Irritation Response Scoring Criteria

[0130] Calculate the average skin response score for each group at each time point, and evaluate the stimulation intensity according to Table 12.

[0131] Table 12 Evaluation Criteria for Skin Irritation Intensity

[0132] Irritation scores were assessed on rabbits after administration of the drug to each group. No erythema or edema was observed at any time point after administration in the blank control group, the low-dose group of test prescription 1 (Example 29), the medium-dose group of test prescription 1 (Example 28), and the high-dose group of test prescription 1. The skin irritation intensity scores were all 0. It can be determined that the patch containing colchicine has no irritation when the colchicine weight percentage is 0.5%, 1%, and 2%.

[0133] Experiment Example 7: Local Tissue Distribution Experiment in Bama Miniature Pigs Eight male Bama miniature pigs were randomly divided into two groups of four each, stratified by weight. Group 1, the patch group, received four colchicine patches per pig per transdermal application to the joints of the limbs once. The patches were prepared according to Example 30 and had a size of 5*7cm per patch. Group 2, the tablet group, received two colchicine tablets (1 mg per pig) per gavage once. These tablets were purchased from Takada Pharmaceutical Co., Ltd., batch number UX10. The formulation information for each group is shown in Table 13.

[0134] Table 13 Formulation Information for Each Group

[0135] Note: The first digit of the animal's number represents its sex (1 for male, 2 for female); the second digit represents its group (1 for group 1, 2 for group 2, and so on); the last two digits represent the animal's serial number.

[0136] At 0.5 h, 2 h, 4 h, and 8 h after drug administration, one animal in each group was dissected, and plasma, liver, kidney, stomach, duodenum, rectum, joint capsules of the four limbs (left anterior, right anterior, left posterior, and right posterior), skin at the joints, and subcutaneous tissue were collected. After weighing the tissue samples collected from Bama miniature pigs, acetonitrile was added at a ratio of 1:3 (w:v, g / mL), and homogenized on a high-throughput tissue homogenizer to prepare Bama miniature pig tissue homogenate.

[0137] The concentration of colchicine in various tissue samples from Bama miniature pigs was quantitatively determined using LC-MS / MS. The distribution of colchicine in the collected tissues at different time points was statistically analyzed, and pharmacokinetic parameters in each tissue and plasma were calculated.

[0138] result: Group 1 patch group: After percutaneous application of colchicine patches to the limb joints of Bama miniature pigs, if... Figure 4-6 As shown, colchicine is mainly distributed in skin tissue, followed by subcutaneous tissue and joint capsules, with relatively less distribution in plasma, liver, kidneys and gastrointestinal tract; The concentrations of colchicine in different tissues at different time points are arranged in the following order: At 0.5 h, the order of quantitation was: skin tissue of the limbs > subcutaneous tissue of the limbs > joint capsule of the limbs. The levels of plasma, liver, kidney, stomach, duodenum, and rectum were all below the lower limit of quantitation. The order of tissue density over 2 hours is: limb skin tissue > limb subcutaneous tissue > limb joint capsule > liver > kidney > plasma > duodenum > stomach > rectum; The order of tissue density over 4 hours is: limb skin tissue > limb subcutaneous tissue > limb joint capsule > duodenum > plasma > liver > kidney > stomach > rectum; The order of tissue composition over 8 hours is: limb skin tissue > limb subcutaneous tissue > limb joint capsule > kidney > liver > duodenum > stomach > rectum > plasma; Total exposure (AUC) 0-8 h The order of the following is: skin tissue of the limbs > subcutaneous tissue of the limbs > joint capsule of the limbs > liver > duodenum > kidney > plasma > stomach > rectum.

[0139] Group 2 (tablet group): After oral administration of colchicine tablets to Bama miniature pigs, if... Figure 7 As shown, colchicine is mainly distributed in the liver, kidneys, and gastrointestinal tract, with relatively less distribution in plasma, skin tissue, subcutaneous tissue, and joint capsules; At 0.5 h, the order of quantification was: duodenum > stomach > limb skin tissue. Plasma, liver, kidney, rectum, limb joint capsules, and limb subcutaneous tissue were all below the lower limit of quantification. The order of tissue distribution over 2 hours is: liver > kidney > duodenum > stomach > rectum > limb skin tissue > plasma > limb subcutaneous tissue > limb joint capsule. The order of 4 hours is: liver > duodenum > kidney > stomach > rectum > limb skin tissue > limb subcutaneous tissue > limb joint capsule > plasma; The order of blood plasma over 8 hours is: liver > kidney > duodenum > stomach > rectum > limb skin tissue > limb subcutaneous tissue > limb joint capsule > plasma. Total exposure (AUC) 0-8 h The order of the following is: duodenum > liver > kidney > stomach > rectum > limb skin tissue > limb subcutaneous tissue > limb joint capsule > plasma.

[0140] Compared with the tablet group, the patch group (Group 1) of Bama miniature pigs showed lower C levels in the liver, kidneys, duodenum, and rectum. max The ratio is between 0.02 and 0.22, AUC 0-8 h The ratios ranged from 0.05 to 0.13, all <1; while the C values ​​of the skin tissue, subcutaneous tissue, and joint capsules of the limbs were... max The ratio ranged from 57.38 to 12866.49, with an AUC of 0-8 h The ratio ranges from 41.54 to 11019.52.

[0141] in conclusion: After transdermal administration of a colchicine-containing patch (11.9 mg / pig) to Bama miniature pigs, colchicine was mainly distributed in the skin tissue, followed by the subcutaneous tissue and joint capsules, with relatively less distribution in plasma, liver, kidneys, and gastrointestinal tract. After oral administration of colchicine tablets (1 mg / pig) to Bama miniature pigs, colchicine was mainly distributed in the liver, kidneys, and gastrointestinal tract, with relatively less distribution in plasma, limb skin tissue, limb subcutaneous tissue, and limb joint capsules. In group 1 (patch group), C-reactive protein (C) was found in the liver, kidneys, duodenum, and rectum. max and AUC 0-8 h All were less than the 2-tablet group, while the C values ​​of the skin tissue, subcutaneous tissue, and joint capsules of the limbs were lower. max and AUC 0-8 h Much larger than the group 2 tablet group.

[0142] This invention provides a colchicine-containing patch, its preparation method, and its application. The patch includes a polymer matrix layer, which, by weight percentage, contains the following components: colchicine 0.1%~5.0%; penetration enhancer 0.005%~15%; and pressure-sensitive adhesive 80%~99%. The colchicine-containing patch of this invention achieves a therapeutic effect through transdermal penetration, exhibits no local irritation or gastrointestinal side effects during and after application, demonstrates high patient compliance, and possesses significant economic value and application prospects.

[0143] 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 patch containing colchicine, characterized in that: The polymer matrix layer comprises, by weight percentage, the following components: Colchicine 0.1%~5.0%, Penetration enhancer 0.005%~15%, Pressure-sensitive adhesive 80%~99%.

2. The patch containing colchicine according to claim 1, characterized in that: The colchicine content in the polymer matrix layer is 0.25% to 4.0% by weight; preferably 0.50% to 3.5%, more preferably 0.50% to 3.0%; and / or The weight percentage of the penetration enhancer in the polymer matrix layer is 0.01%~12%; and / or The weight percentage of pressure-sensitive adhesive in the polymer matrix layer is 85% to 98%.

3. The patch containing colchicine according to claim 1, characterized in that: The patch also includes a backing layer; Preferably, the patch further includes a protective layer, with the polymer matrix layer located between the backing layer and the protective layer.

4. The colchicine-containing patch according to any one of claims 1-3, characterized in that: The penetration enhancer is selected from reagents that can dissolve colchicine and have a boiling point greater than or equal to 150°C; Preferably, the reagent is selected from one or more of alcohols, alkanolamines, and alcohol ethers; Preferably, the boiling point of the reagent is greater than or equal to 180°C; Preferably, the alcohols are selected from monohydric alcohols and / or dihydric alcohols; Preferably, the monohydric alcohol is selected from one or more of lauryl alcohol, oleyl alcohol, and terpineol; Preferably, the diol is selected from oxadiol; Preferably, the alkanolamine is selected from one or more of tromethamine, ethanolamine, diethanolamine, triethanolamine, N-hydroxyethylpiperidine, N-hydroxyethylpyrrolidine, N-hydroxyethylpiperazine, N,N-dibutylaminoethanol, and N,N-diethylaminoethanol; Preferably, the alcohol ether is selected from one or more of diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monohexyl ether, dipropylene glycol methyl ether, dipropylene glycol butyl ether, and dipropylene glycol condensate.

5. The patch containing colchicine according to claim 3, characterized in that: The backing layer is selected from closed backing films or non-closed backing films; Preferably, the backing layer is selected from closed backing films; Preferably, the closed backing film is selected from light-shielding closed backing films; Preferably, the closed backing film is selected from a polyester-polyethylene composite film with a metal aluminum liner; Preferably, the thickness of the closed backing film is 20~100μm; Preferably, the protective layer is selected from release film.

6. The colchicine-containing patch according to any one of claims 1-3, characterized in that: The pressure-sensitive adhesive is selected from one or two of acrylic pressure-sensitive adhesives and polysilicon pressure-sensitive adhesives.

7. The colchicine-containing patch according to any one of claims 1-3, characterized in that: The colchicine content in the polymer matrix layer ranges from 10 μg / cm³. 2 ~150μg / cm 2 ; Preferably, the application area of ​​the colchicine-containing patch is 5 cm². 2 ~100cm 2 .

8. A method for preparing a patch containing colchicine as described in any one of claims 1-7, characterized in that: Includes the following steps: (1) Dissolve the prescribed amount of colchicine and penetration enhancer in an organic solvent to obtain a mixture; (2) Add the mixture obtained in step (1) to the prescribed amount of pressure-sensitive adhesive to obtain the adhesive solution; (3) Apply the adhesive obtained in step (2) onto the protective layer and remove the organic solvent; (4) The product obtained in step (3) is combined with the backing layer and punched to obtain a patch containing colchicine.

9. A method for preparing a patch containing colchicine as described in any one of claims 1-7, characterized in that: Includes the following steps: (1) Add the prescribed amounts of colchicine, penetration enhancer and pressure-sensitive adhesive to an organic solvent and mix to obtain an adhesive solution; (2) Apply the adhesive obtained in step (1) onto the protective layer and remove the organic solvent; (3) The product obtained in step (2) is combined with the backing layer and punched to obtain a patch containing colchicine.

10. The method for preparing the colchicine-containing patch according to claim 8 or 9, characterized in that: The organic solvent in step (1) is selected from one or more of methanol, ethanol, and isopropanol; Preferably, the specific operation for removing the organic solvent is as follows: drying at 35~50℃ to remove the organic solvent.

11. The use of a colchicine-containing patch as described in any one of claims 1-7 in the preparation of a medicament for the prevention and / or treatment of gout and / or pericarditis.

Images