Colchicine-containing patch, its preparation method and use

Abstract

The present invention relates to a colchicine-containing patch comprising a polymer matrix layer containing the following components by weight: 0.1% to 5.0% colchicine, 0.005% to 15% permeation enhancer, and 80% to 99% pressure-sensitive adhesive, as well as a preparation method and use thereof. The colchicine-containing patch of the present invention is capable of achieving a therapeutically effective dose through transdermal penetration, is free from local irritation during and after application, is free from gastrointestinal side effects, and ensures high patient compliance.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Chinese Patent Application No. 202211213655.8, filed on September 30, 2022, entitled "Colchicine-containing patch, its preparation method and use," the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to the technical field of transdermal administration, and specifically to a colchicine-containing patch, its preparation method and use. [Background technology]

[0003] Colchicine has the chemical name N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[α]cycloheptatrienocycloheptatrien-7-yl)-(S)-acetamide and the molecular formula C 22 H 25 It is NO6, has a molecular weight of 399.4, is a pale yellow to pale greenish yellow, amorphous or crystalline powder, is odorless, and darkens when exposed to light. Its chemical structure is as follows: [ka]

[0004] Colchicine has a specific tricyclic ring structure and is unstable under high temperature and light exposure conditions, particularly under light exposure, producing genotoxic impurities C and G. The chemical structures of impurities C and G are as follows: [ka]

[0005] Colchicine, a natural plant alkaloid, has been used by humans since prehistoric times. Its pure, purified form was first extracted from the Colchicum plant in 1820. It is currently approved for the prevention and treatment of gout by major drug regulatory agencies, including the FDA, PDMA, EMA, and NPMA. Gout is the second most common metabolic disease after diabetes, and colchicine is currently the first-line treatment and preventative for acute gout attacks. In addition to gout, colchicine is also used to treat and prevent cardiovascular diseases such as Mediterranean fever and pericarditis, and skin conditions such as Sweet's syndrome and psoriasis.

[0006] However, colchicine has a narrow therapeutic safety margin because its therapeutic dose is close to the toxic dose, and its bioavailability is low due to the first-pass effect in the liver. All currently approved oral colchicine formulations are associated with serious side effects, including abdominal pain, nausea, vomiting, diarrhea, bone marrow suppression, arrhythmia, and azoospermia. Therefore, although colchicine is highly clinically effective, more than 80% of patients are unable to continue oral administration of colchicine due to these serious side effects.

[0007] A transdermal drug delivery system (TDDS) is a drug delivery method in which drugs are absorbed through the skin or mucous membranes and delivered to the local treatment site or the whole body. The transdermal administration method has many advantages, such as no gastrointestinal irritation, avoiding the first-pass effect in the liver, being non-invasive, sustained-release, reducing the number of frequent administrations, and avoiding fluctuations in blood drug concentration due to oral absorption, and therefore has higher safety and better patient compliance.

[0008] However, although several attempts to administer colchicine transdermally have been reported in the literature, the clinical requirements for high colchicine safety and good compliance have not been met, and there is an urgent need to develop a transdermal administration system that can safely and effectively deliver colchicine. Summary of the Invention [Problem to be solved by the invention]

[0009] The technical problem to be solved by the present invention is to overcome the drawbacks of the prior art and provide a colchicine-containing patch comprising a polymer matrix layer containing the following components by weight: 0.1%-5.0% colchicine, 0.005%-15% penetration enhancer, and 80%-99% pressure-sensitive adhesive, as well as a preparation method and use thereof. The colchicine-containing patch of the present invention is capable of achieving a therapeutically effective amount through transdermal penetration, is free from local irritation during and after application, is free from gastrointestinal side effects, and ensures high patient compliance. [Means for solving the problem]

[0010] In order to solve the above technical problems, the present invention employs the following technical solutions.

[0011] On the other hand, the present invention provides a composition comprising the following components: Colchicine 0.1% to 5.0% Penetration enhancer 0.005% to 15% Pressure sensitive adhesive 80%~99% The colchicine-containing patch comprises a polymer matrix layer containing the following in weight percent:

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

[0013] Preferably, in the polymer matrix layer, the weight percentage of the penetration enhancer is 0.01% to 12%, and specifically may 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%, or 10.00%.

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

[0015] Preferably, the colchicine-containing patch further comprises a backing layer.

[0016] Preferably, the colchicine-containing patch further comprises a protective layer, and the polymeric matrix layer is located between the backing layer and the protective layer.

[0017] Preferably, the penetration enhancer is selected from agents capable of dissolving colchicine and having a boiling point of 150° C. or higher.

[0018] Preferably, the penetration enhancer is selected from one or more of alcohols, alcohol amines and alcohol ethers.

[0019] Preferably, the penetration enhancer has a boiling point of 180°C or greater.

[0020] Preferably, the alcohols are selected from monohydric and / or dihydric alcohols.

[0021] Preferably, the monohydric alcohol is selected from one or more of lauryl alcohol, oleyl alcohol and terpineol.

[0022] Preferably, the dihydric alcohol is selected from hexanediol.

[0023] Preferably, the alcoholamines are selected from one or more of tromethamine, ethanolamine, diethanolamine, triethanolamine, N-hydroxyethylpiperidine, N-hydroxyethylpyrrolidine, N-hydroxyethylpiperazine, N,N-dibutylaminoethanol and N,N-diethylaminoethanol.

[0024] Preferably, the alcohol ethers are 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.

[0025] Preferably, the backing layer is selected from an occlusive backing film or a non-occlusive backing film.

[0026] Preferably, the backing layer is selected from closed-type backing films.

[0027] Preferably, the closed backing film is selected from light-tight closed backing films.

[0028] Preferably, the occlusive backing film is selected from metallic aluminum backed polyester / polyethylene composite films.

[0029] Preferably, the closed backing film has a thickness of 20 to 100 μm.

[0030] Preferably, the protective layer is selected from a release liner.

[0031] Preferably, the pressure sensitive adhesive is selected from one or more of an acrylic pressure sensitive adhesive or a silicone pressure sensitive adhesive, and more preferably, the pressure sensitive adhesive is selected from one or two of an acrylic pressure sensitive adhesive or a silicone pressure sensitive adhesive.

[0032] Preferably, the content of colchicine in the polymer matrix layer is 10 μg / cm 2 ~150μg / cm 2 The range is.

[0033] Preferably, the administration area of the colchicine-containing patch is 5 cm 2 ~100cm 2 is.

[0034] On the other hand, the present invention (1) dissolving a prescribed dose of colchicine and a penetration enhancer in an organic solvent to obtain a mixed solution; (2) adding the mixed solution obtained in step (1) dropwise to a prescribed amount of pressure-sensitive adhesive to obtain an adhesive solution; (3) applying the adhesive solution obtained in step (2) to the protective layer and removing the organic solvent; (4) A step of laminating the product obtained in step (3) with a backing layer and punching the laminate to obtain a colchicine-containing patch. The present invention also provides a method for preparing a colchicine-containing patch according to the present invention, which comprises:

[0035] On the other hand, the present invention is (1') adding a prescribed amount of colchicine, a penetration enhancer, and a pressure-sensitive adhesive to an organic solvent and mixing to obtain an adhesive solution; (2') applying the adhesive solution obtained in step (1') to the protective layer and removing the organic solvent; (3') laminating the product obtained in step (2') with a backing layer and punching the resulting mixture to obtain a colchicine-containing patch; The present invention provides a method for preparing a colchicine-containing patch according to the present invention, comprising:

[0036] Preferably, the organic solvent in step (1) and / or step (1') is selected from one or more of methanol, ethanol or isopropanol.

[0037] Preferably, the specific operation for removing the organic solvent in step (3) and / or step (2') is to remove the organic solvent by drying under conditions of 35 to 50°C.

[0038] On the other hand, there is provided the use of a colchicine-containing patch according to the present invention in the preparation of a medicament for preventing and / or treating gout and / or pericarditis.

[0039] The present invention further provides a method for treating gout and / or pericarditis, comprising administering a therapeutically effective amount of a colchicine-containing patch according to the present invention to a subject in need thereof.

[0040] The present invention further provides a colchicine-containing patch according to the present invention for preventing and / or treating gout and / or pericarditis. [Effects of the Invention]

[0041] By using the above technical means, the present invention has the following advantages over the prior art. 1. The colchicine content in the colchicine-containing patch of the present invention can achieve a therapeutically effective amount through transdermal penetration, does not cause local skin irritation during or after application, has no gastrointestinal side effects, and achieves high patient compliance. 2. The penetration enhancer of the present invention facilitates the transdermal penetration of colchicine to achieve a sustained and controllable therapeutically effective dose, and has good compatibility with the colloid matrix. 3. The colchicine-containing patch of the present invention comprises a backing layer directly connected to the polymer matrix layer, and the backing layer serves to protect the polymer matrix layer from contact with the surrounding environment during use and prevent loss of the drug. 4. The backing layer of the present invention is preferably a light-shielding closed-type backing film, which has well-controllable permeability and maintains the colloidal matrix in good condition after application, thereby maintaining good application performance and meeting the application requirements of the patch during use. Therefore, the light-shielding backing film can reduce or eliminate the risk of photodecomposition of colchicine, and can prevent it. [Brief explanation of the drawings]

[0042] [Figure 1a] 1 is a phase diagram of colchicine at different contents dissolved in 4098 pressure-sensitive adhesive for 0 days. [Figure 1b] 1 shows the phase diagram of 4098 pressure-sensitive adhesive with different colchicine loadings after 4 months at room temperature. [Figure 2] FIG. 10 shows the results of an in vitro penetration experiment for the patch of Example 24. [Figure 3] FIG. 10 shows the results of an in vivo penetration experiment for the patch of Example 24. [Figure 4] FIG. 1 shows the concentration in each tissue or plasma of male Bama miniature pigs to which the colchicine-containing patch of the present invention was administered transdermally once at a dose of 11.9 mg / pigs. [Figure 5] FIG. 5 is a partially enlarged view of FIG. [Figure 6] FIG. 5 is a partially enlarged view of FIG. [Figure 7] FIG. 1 shows the concentration of colchicine in each tissue or plasma of male Bama miniature pigs after a single intragastric administration of a colchicine tablet at a dose of 1 mg / animal. DETAILED DESCRIPTION OF THE INVENTION

[0043] The present invention comprises the following components: Colchicine 0.1% to 5.0% Penetration enhancer 0.005% to 15% Pressure sensitive adhesive 80%~99% The colchicine-containing patch includes a polymer matrix layer containing the following in weight percent:

[0044] Colchicine has a certain degree of skin irritation, which is directly related to the colchicine content, as well as 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. Therefore, to ensure a therapeutic penetration dose while reducing or eliminating local skin irritation at the application site of a colchicine-containing patch, in some specific embodiments, the weight ratio of colchicine to the dry weight of the polymeric matrix layer may be 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%, or 3.0%. At these levels, the colchicine-containing patch can be continuously and controllably delivered to achieve a therapeutically effective dose during application, while simultaneously reducing or eliminating local skin irritation.

[0045] The present invention contains a penetration enhancer to achieve a therapeutic dose of colchicine. Due to its specific structure, colchicine has excellent water solubility and is generally soluble in alcohols and their derivatives, but insoluble in low-polarity solvents such as ethyl acetate. However, the pressure-sensitive adhesive system used in the present invention uses ethyl acetate as the primary solvent, so not all types of penetration enhancers can achieve the objectives of the present invention. Therefore, one of the problems to be solved by the present invention is to select a suitable penetration enhancer that can promote the transdermal permeation of colchicine to achieve a therapeutically effective dose and simultaneously dissolve or disperse colchicine uniformly in a colloidal matrix containing ethyl acetate as the primary solvent.

[0046] In some specific embodiments, penetration enhancers include, but are not limited to, alcohols such as methanol, ethanol, diethanol, terpineol, oleyl alcohol, camphor, borneol, and the like; alcohol ethers such as diethylene glycol monomethyl ether, alcohol amines such as triethanolamine, N-hydroxyethylpyrrolidine, and the like; dimethyl sulfoxide (DMSO), N-methylpyrrolidone, oleic acid, and the like.

[0047] The present invention unexpectedly found that in transdermal drug delivery systems, some penetration enhancers have a penetration-enhancing effect, but there is also a potential risk of destroying the colloidal properties of the pressure-sensitive adhesive, especially when added at a higher content. For example, in some specific examples, after adding a portion of the penetration enhancer, the pressure-sensitive adhesive in solution state partially changes to a gel state or partially becomes lumpy, resulting in a change in the rheology of the colloid and further leading to coating failure. In some specific examples, as the content of the penetration enhancer increases, the colloidal properties are further destroyed. Therefore, the present invention selects a penetration enhancer taking into account both the penetration-enhancing effect and the colloidal properties. The present invention 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.

[0048] In some specific embodiments, the penetration enhancer is selected from agents capable of dissolving colchicine and having a boiling point of 150° C. or higher.

[0049] In some specific embodiments, the penetration enhancer is selected from one or more of alcohols, alcohol amines, and alcohol ethers.

[0050] In some specific embodiments, the penetration enhancer has a boiling point of 180°C or greater.

[0051] In some specific embodiments, the alcohols are selected from monohydric alcohols and / or dihydric alcohols.

[0052] In some specific examples, monohydric alcohols include, but are not limited to, lauryl alcohol, oleyl alcohol, and terpineol; dihydric alcohols include, but are not limited to, hexanediol; alcohol amines include, but are not limited to, tromethamine, ethanolamine, diethanolamine, triethanolamine, N-hydroxyethylpiperidine, N-hydroxyethylpyrrolidine, N-hydroxyethylpiperazine, N,N-dibutylaminoethanol, 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, dipropylene glycol, and the like.

[0053] In some specific embodiments, penetration enhancers may be used alone or in combination.

[0054] Penetration enhancers not only enhance the penetration of colchicine, but also increase the solubility of colchicine in the colloid matrix. Therefore, the solubility of colchicine in the colloid matrix tends to increase after the addition of a penetration enhancer. Another implication of increased solubility is that the same amount of colchicine is less likely to reach or approach its maximum saturated solubility. However, the thermodynamic passive diffusion capacity of colchicine is directly related to the degree of approach to saturated solubility, and generally, the thermodynamic passive diffusion capacity is highest when the maximum saturated solubility is reached or approached. Therefore, adding a solubilizing penetration enhancer increases the solubility of colchicine in the colloid matrix and reduces its thermodynamic passive diffusion capacity to some extent.

[0055] Therefore, the penetration enhancing ability is related not only to the type of penetration enhancer but also to the content of the penetration enhancer. Therefore, in certain embodiments, adding a penetration enhancer may actually decrease the penetration ability and not achieve the penetration enhancing effect. It is generally known in the art that the penetration ability can be increased by further increasing the colchicine content range to reach or approach the saturated solubility. However, because colchicine has local skin irritation related to its content, there is a limit to how much the penetration ability can be increased by further increasing the colchicine content range in the colloidal matrix to reach or approach the saturated solubility.

[0056] In some specific embodiments, the weight ratio of the penetration enhancer to the dry weight of the polymeric matrix layer may be 0.005% to 15%, preferably 0.01% to 12%, such as 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%, or 10.00%.

[0057] The pressure-sensitive adhesive is selected from pressure-sensitive adhesives pharmaceutically suitable for transdermal drug delivery systems, and in some specific embodiments is selected from one of an acrylic-based pressure-sensitive adhesive based on an acrylic polymer compound or a silicone-based pressure-sensitive adhesive based on a silicone polymer compound.

[0058] In some specific examples, the acrylic pressure-sensitive adhesive may be any homopolymer, copolymer, trimer, or polymer of different acrylic acids. Depending on the functional groups contained, it may be a non-functionalized acrylic pressure-sensitive adhesive or a functionalized acrylic pressure-sensitive adhesive, including, but not limited to, hydroxyl, carboxyl, or both hydroxyl and carboxyl, amino, epoxy, etc. In some examples, the type and dosage of the acrylic pressure-sensitive adhesive may vary depending on the amount of colchicine active ingredient added and the therapeutically effective amount desired to be delivered, and may be selected from functionalized acrylic pressure-sensitive adhesives, non-functionalized acrylic pressure-sensitive adhesives, or a mixture of both.

[0059] In some specific embodiments, the weight ratio of the acrylic pressure-sensitive adhesive to the dry weight of the polymer matrix layer may be 80% to 99%, preferably 85% to 98%, specifically 85%, 90%, 95%, or 98%.

[0060] Commercially available acrylic pressure-sensitive adhesives include Duro-Tak 87-900A, Duro-Tak 87-9301 (non-crosslinked vinyl acetate acrylic pressure-sensitive adhesive, no functional groups), Duro-Tak 87-4098 (non-crosslinked vinyl acetate acrylic pressure-sensitive adhesive, no functional groups), Duro-Tak 87-2287 (non-crosslinked vinyl acetate acrylic pressure-sensitive adhesive, with hydroxyl functionality), Duro-Tak 87-2852 (crosslinked acrylic pressure-sensitive adhesive, with carboxyl functionality), Duro-Tak 87-2196 (crosslinked acrylic pressure-sensitive adhesive, with carboxyl functionality), Duro-Tak 87-2296 (crosslinked acrylic pressure-sensitive adhesive, with carboxyl functionality), Duro-Tak 87-2194 (crosslinked acrylic pressure-sensitive adhesive, with carboxyl functionality), and Duro-Tak Duro-Tak products by Henkel include 87-2516 (crosslinked acrylic pressure-sensitive adhesive with carboxyl functionality), Duro-Tak 87-2070 (crosslinked acrylic pressure-sensitive adhesive with carboxyl functionality), Duro-Tak 87-2353 (non-crosslinked acrylic pressure-sensitive adhesive with carboxyl functionality), Duro-Tak 87-2154 (crosslinked acrylic pressure-sensitive adhesive with carboxyl functionality), and Duro-Tak 87-2510 (non-crosslinked acrylic pressure-sensitive adhesive with hydroxyl functionality).

[0061] In some specific embodiments, the weight ratio of the silicone-based pressure-sensitive adhesive to the dry weight of the polymer matrix layer may be 90% to 99%, preferably 95% to 99%, specifically 95%, 96%, 97%, 98%, or 99%.

[0062] Commercially available silicone 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.

[0063] Due to the physicochemical properties of colchicine, its solubility in acrylic pressure-sensitive adhesives is high, while its solubility in polysilicone pressure-sensitive adhesives is low. In some specific embodiments, the pressure-sensitive adhesive can be selected from a mixture of an acrylic pressure-sensitive adhesive and a polysilicone pressure-sensitive adhesive. When using a mixture of an acrylic pressure-sensitive adhesive and a polysilicone pressure-sensitive adhesive, the mixing ratio of the two can be adjusted taking into consideration the overall penetration ability and safety of colchicine. Methods for mixing an acrylic pressure-sensitive adhesive and a polysilicone pressure-sensitive adhesive include physical mixing, i.e., mixing two types of pressure-sensitive adhesives with different properties and stirring to form a uniformly dispersed suspension, and chemical synthesis to obtain a mixed acrylic and silicone pressure-sensitive adhesive.

[0064] In some specific embodiments, the pressure-sensitive adhesive ratio of the mixture of acrylic pressure-sensitive adhesive and silicone pressure-sensitive adhesive to the dry weight of the polymer matrix layer may be 90% to 99%, preferably 95% to 99%, specifically 95%, 96%, 97%, 98%, or 99%, and the dry adhesive weight ratio of the acrylic pressure-sensitive adhesive to the silicone pressure-sensitive adhesive may be 30 to 70:70 to 30, specifically 50:50, 40:60, 60:40, 30:70, or 70:30.

[0065] In some specific embodiments, the colchicine-containing patch further comprises a backing layer and a protective layer, and the polymeric matrix layer is positioned between the backing layer and the protective layer.

[0066] The backing layer is directly connected to one surface of the polymeric matrix layer, and during use, the backing layer protects the polymeric matrix layer from contact with the surrounding environment and prevents loss of the drug.

[0067] The protective layer is selected from a release liner and is directly attached to the other surface of the polymeric matrix layer, and the release liner is removed from the patch before use.

[0068] 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 backed with metal foils such as metallic aluminum, nonwoven fabrics, elastic fabrics, and the like.

[0069] Since colchicine is highly water-soluble, water breathed by the skin at the application site during application enters the colloidal matrix, thereby affecting the solubility of such water-soluble components in the colloidal matrix, and consequently affecting their thermodynamic diffusion ability, i.e., penetration ability and application performance. The extent of this effect depends on the application time and the properties of the backing film.

[0070] Therefore, in order to solve the effect of water generated by skin respiration during application on the permeation behavior and application performance of the patch, in some specific embodiments of the present invention, the backing layer is selected from an occlusive backing film or a non-occlusive backing film.

[0071] Closed and non-closed backing films are classified based on their permeability to water and oxygen. Non-closed backing films, such as nonwoven fabrics and elastic fabrics, have a certain degree of permeability to oxygen and water caused by skin respiration, while closed backing films, such as aluminum-backed polyester / polyethylene composite films, have a very low permeability to water and oxygen and act as a barrier to oxygen and water caused by skin respiration. The permeability to water and oxygen can be adjusted by adjusting the properties and thickness of the backing film material.

[0072] In some specific embodiments, the backing layer is selected from non-occlusive backing films, which facilitate water evacuation, reduce the decrease in the thermodynamic permeability of colchicine, and maintain permeability, but after a certain period of application, the colloidal matrix may partially remain on the skin, resulting in poor peeling.

[0073] In some specific embodiments, the backing layer is selected from a closed backing film, which has good controllable permeability and maintains good adhesion performance by maintaining a good state of the colloidal matrix after application, and the thickness of the closed backing film is 20 to 100 μm, preferably 20 to 80 μm.

[0074] In some specific embodiments, the closed backing film is selected from a polyester / polyethylene composite film backed with metallic aluminum, and has a thickness of 20 to 100 μm, preferably 20 to 80 μm.

[0075] In some specific embodiments, the backing film is selected from ScotchPak™ 1109, ScotchPak™ 9738, or ScotchPak™ 9730 by 3M Company, preferably ScotchPak™ 9738.

[0076] In some specific embodiments, the content of colchicine in the polymer matrix layer is 10 μg / cm 2 ~150μg / cm 2 and specifically, 15 μg / cm 2 ~120μg / cm 2 , 20 μg / cm 2 ~100μg / cm 2 , 20 μg / cm 2 ~25μg / cm 2 , 30 μg / cm 2 ~35μg / cm 2 , more specifically, 20 μg / cm 2 , 25 μg / cm 2, 30 μg / cm 2 , 35 μg / cm 2 , 40 μg / cm 2 , 45 μg / cm 2 , 50 μg / cm 2 , 55 μg / cm 2 , 60 μg / cm 2 , 65 μg / cm 2 , 70 μg / cm 2 , 75 μg / cm 2 , 80 μg / cm 2 , 85 μg / cm 2 , 90 μg / cm 2 , 100 μg / cm 2 There may be some other ranges such as:

[0077] In some specific embodiments, the administration area of the colchicine-containing patch is determined according to the blood concentration or clinical effect to be achieved within the application time. 2 ~100cm 2 Specifically, 10cm 2 ~90cm 2 , more specifically, 10cm 2 , 15cm 2 , 20cm 2 , 30cm 2 , 40cm 2 , 50cm 2 , 60cm 2 , 70cm 2 , 80cm 2 There may be some other ranges such as:

[0078] In some specific embodiments, the method for preparing a colchicine-containing patch according to the present invention comprises: (1) dissolving a prescribed dose of colchicine and a penetration enhancer in an organic solvent to obtain a mixed solution, wherein the weight ratio of colchicine to the organic solvent is 1:1; (2) a step of uniformly stirring the mixed solution obtained in step (1) and then adding the mixed solution dropwise to a prescribed amount of pressure-sensitive adhesive at room temperature at an appropriate speed to obtain an adhesive solution; (3) a step of uniformly stirring the adhesive solution obtained in step (2), applying it to a protective layer (release liner), and drying the applied polymer matrix layer at a predetermined temperature to remove the organic solvent; (4) laminating the product obtained in step (3) with a backing layer and punching it according to the required specifications to obtain a colchicine-containing patch; Includes:

[0079] In some specific embodiments, the method for preparing a colchicine-containing patch according to the present invention comprises: (1') adding a prescribed amount of colchicine, a penetration enhancer, and a pressure-sensitive adhesive to an organic solvent and mixing to obtain an adhesive solution; (2') a step of uniformly stirring the adhesive solution obtained in step (1'), applying it to a protective layer (release liner), and drying the applied polymer matrix layer at a predetermined temperature to remove the organic solvent; (3') laminating the product obtained in step (2') with a backing layer and punching it according to the required specifications to obtain a colchicine-containing patch; Includes:

[0080] In some specific embodiments, the organic solvent in step (1) and / or step (1') is selected from one or more of methanol, ethanol, or isopropanol, preferably ethanol.

[0081] In some specific examples, the specific operation for removing the organic solvent in step (3) and / or step (2') is to remove the organic solvent from the applied polymer matrix layer by drying it under conditions of 35 to 50°C.

[0082] It should be noted that the procedure for preparing the above-mentioned patch, the amount of each component added, the stirring time, the stirring speed, and other parameters vary depending on the required end use. The above parameters can be adjusted as needed.

[0083] An exemplary preparation method is as follows. Step 1): First, weigh the prescribed dose of colchicine and penetration enhancer, dissolve them in an appropriate amount of ethanol while stirring, and then stir for 15 to 60 minutes depending on the amount added to obtain a mixed solution. Step 2): The mixed solution obtained in step 1) is added dropwise to the prescribed amount of pressure-sensitive adhesive while stirring, and stirring is continued for 10 to 60 minutes to obtain an adhesive solution; Step 3): After uniformly stirring the adhesive solution obtained in step 2), apply it to a release liner in a thickness that depends on the final clinical use, and then dry it in an oven with an exhaust function at 35-50°C for 5-15 minutes to remove the organic solvent. The specific drying temperature and time are determined by the coating speed and the amount of residual solvent. Step 4): The product obtained in step 3) is laminated with a selected backing film and punched according to the required specifications to obtain a colchicine-containing patch.

[0084] Other methods reported in the literature can also be used to prepare the patch of the present invention based on common methods for preparing patches.

[0085] In some specific examples, the use of the patch of the present invention in the preparation of a medicament for preventing and / or treating gout and / or pericarditis is disclosed.

[0086] Explanation of terms: Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly used in the art to which this invention belongs. For the purposes of interpreting this specification, the following definitions shall apply, and where appropriate, terms used in the singular shall also include the plural and vice versa.

[0087] The terms "transdermal administration" or "transdermal drug delivery" as used herein refer to a dosage form in which an active ingredient is delivered locally or systemically through the skin or mucous membranes. In the present patent, they have the same meaning and are used interchangeably.

[0088] The terms "polymeric matrix layer" or "colloidal matrix layer" used in the present invention refer to the combination of a polymeric pressure-sensitive adhesive, colchicine, and any other pharmaceutically acceptable adjuvants contained in the transdermal drug delivery system. Generally, the polymeric matrix layer is located between a release liner and a backing film. The polymeric matrix layer functions as the drug delivery layer of the transdermal drug delivery system, forming an adhesive-drug mixed transdermal drug delivery system. The polymeric matrix layer and colloidal matrix layer of the present invention have the same meaning and are used interchangeably.

[0089] The term "transdermal patch" or "transdermal drug delivery system" as used herein refers to a system containing an active ingredient for transdermal administration, and generally includes a backing layer, a release liner, and a polymeric matrix dosage layer positioned between the two layers. Depending on the combination of the active ingredient and other ingredients in the polymeric matrix dosage layer, they are generally classified into reservoir types and adhesive / drug combination types. Transdermal drug delivery systems may be abbreviated as "patch" or "transdermal patch," and these terms may be used interchangeably in the present invention. The polymeric matrix dosage layer generally comprises the active ingredient, penetration enhancers and / or other pharmaceutical excipients suitable for transdermal drug delivery patches, including, but not limited to, pressure-sensitive adhesives, fillers, crosslinkers, antioxidants, UV absorbers, antibacterial agents, etc.

[0090] The term "permeability" as used in the present invention refers to the passive diffusion of a drug through the skin or mucous membrane, and the driving force is the difference in the concentration of the active ingredient on both sides of the skin. The cumulative amount of permeation per unit time and unit area can be used as an index for evaluating the permeability of a patch, and is generally μg / cm 2 It is expressed as flux in units of / hr.

[0091] The term "pressure-sensitive adhesive" as used herein refers to a type of viscoelastic polymeric material that, when contacted with the surface of most other materials, adheres to them with light pressure and maintains its adhesive strength for a long period of time. There are generally two types of pressure-sensitive adhesives: one is a pressure-sensitive adhesive itself, and the other is one that can be made to function as a pressure-sensitive adhesive by adding a tackifier or plasticizer. Pressure-sensitive adhesives have good physical properties at room temperature, such as good adhesion to skin, maintaining adhesion for a certain period of time, being able to be peeled off without damaging the skin, and having a controllable degree of cold flow, thereby meeting adhesion requirements. Common types include acrylic-based pressure-sensitive adhesives, silicone-based pressure-sensitive adhesives, and rubber-based pressure-sensitive adhesives. These pressure-sensitive adhesives can also be physically mixed or chemically bonded to form new mixed pressure-sensitive adhesives to adjust their properties and meet specific requirements.

[0092] The term "backing layer" as used herein refers to a layer in a transdermal patch that is impermeable to drugs. One surface of the backing layer is directly connected to the polymer matrix layer, protecting the polymer matrix layer from contact with the surrounding environment and preventing drug loss during use. The material corresponding to the backing layer is generally called a backing film. Materials for the backing layer generally include polyester, polyethylene / polyvinyl acetate composite film, polyvinyl chloride, polyurethane, metal foil composite film, nonwoven fabric, and elastic fabric, and their thickness is generally 10-200 μm. For example, ScotchPak™ 9730, 9701, 9720, and 9723 from 3M Corporation in the United States, elastic fabric 6015A from Xiaoshan, China, EW2080 and EW2083 from Vilene Nonwovens in Japan, and PE3601 from SHANGHAI YIGKE can be used. Backing films with different properties differ in physicochemical properties such as ductility, air permeability, oxygen permeability, and light blocking properties, and are classified into closed-type backing films and non-closed-type backing films. The backing layer and backing film of the present invention have the same meaning and are used interchangeably.

[0093] The term "light-tight occlusive backing film" as used herein refers to a backing film that has very low permeability to water, oxygen, light, etc., and is generally made of metal foils of various thicknesses, such as aluminum foil.

[0094] The term "release liner" as used in the present invention is directly connected to the other surface of the polymeric matrix layer, and is also called a protective layer. The release liner is removed from the transdermal patch before use.

[0095] The terms "osmotically effective dose," "osmotically therapeutically effective amount," or "effectiveness" as used herein refer to the ability of a transdermal patch to deliver a required amount of active ingredient through the skin during use to act locally or systemically to achieve a specific pharmacological effect, such as curing, alleviating, or controlling a disease or symptom. In the present invention, these terms can be used interchangeably.

[0096] The term "colchicine" as used in the present invention refers to a tropolone alkaloid present in the lily plant Colchicum, which exerts its corresponding pharmacological role by inhibiting cell division.

[0097] The term "penetration enhancer" as used herein refers to a substance that can modify the rate of diffusion of an active ingredient into the skin, and is usually miscible with the active ingredient and uniformly dispersed in the polymer matrix layer.

[0098] The term "adhesion performance" as used in the present invention refers to all processes, including the peel force required to peel the patch from the release liner, the peel force required to peel the patch from the application site after application, tack, shear retention, cold flow, etc. Among these, "peel" refers to the force required to peel the backing layer consisting of a polymer matrix layer from the release liner or to peel the patch from the skin after application. To avoid poor peeling or colloid residue on the skin, the peel force must not be too strong. "tack" refers to the penetration of the backing layer consisting of a polymer matrix layer into the application site and can reduce the risk of peeling during application. "shear" refers to the degree of displacement of the patch at the application site and reflects the adhesion strength during application. "Cold flow" refers to the viscoelastic creep of the polymer matrix layer. These factors may cause black spots to form during application of the patch or the patch to adhere to the protective layer or packaging container during storage, affecting patient safety and efficacy. In general, it is necessary to balance properties such as peel strength, tack, shear retention, and cold flow of the patch.

[0099] The term "colloidal properties" as used herein refers to the properties of the pressure-sensitive adhesive solution formed when all raw materials and adjuvants are added to the pressure-sensitive adhesive and formulated during the formulation development process, such as changes in rheology, coatability, etc.

[0100] As used herein, the term "about" refers to a range of ±20% of the preceding numerical value. In some embodiments, the term "about" refers to a range of ±10% of the preceding numerical value. In some embodiments, the term "about" refers to a range of ±5% of the preceding numerical value.

[0101] In order to make the technical solutions and beneficial effects of the present invention clearer and easier to understand, the following detailed description is given with specific examples in conjunction with the accompanying drawings. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. If specific techniques or conditions are not specified in the examples, they will usually follow the conventional techniques or conditions described in the literature of the technical field or follow the product specifications. Unless otherwise specified, all reagents, materials, or instruments used are conventional products that can be purchased through official commercial channels.

[0102] In the following examples and experimental examples, the model numbers and abbreviations of the pressure-sensitive adhesives are as shown in Table 1.

[0103] Table 1. List of pressure-sensitive adhesive model numbers and abbreviations [Table 1]

[0104] Here, numbers 1 to 11 are all polyacrylic pressure-sensitive adhesives manufactured by Henkel. Liveo™ BIO-PSA 7-4302 is a silicone-based pressure-sensitive adhesive, and Liveo™ 7-6302 SilAc Hybrid PSA is a polyacrylic acid and silicone hybrid pressure-sensitive adhesive, both of which are commercially available from DuPont. For ease of description, the examples and experimental examples of the present invention omit the alphabetical portion of each pressure-sensitive adhesive and use only the abbreviated number.

[0105] In the following Examples and Experimental Examples, the English abbreviations are as shown in Table 2.

[0106] Table 2. List of English abbreviations [Table 2]

[0107] The colchicine-containing patch of the present invention comprises a backing layer, a protective layer, and a polymer matrix layer, the polymer matrix layer containing colchicine, a penetration enhancer, and a pressure-sensitive adhesive, and is located between the backing layer and the protective layer, wherein the backing layer is selected from a light-blocking occlusive backing film, the protective layer is selected from a release liner, and the penetration enhancer dissolves the active ingredient and simultaneously has a penetration enhancing effect.

[0108] Example 1: Solubility of colchicine active ingredient in different types of pressure-sensitive adhesives Colchicine was dissolved at different concentrations in pressure-sensitive adhesive systems with different properties, and the results are shown in Table 3.

[0109] Table 3. Solubility of colchicine active ingredient in different pressure-sensitive adhesives [Table 3]

[0110] The results in Table 3 show that colchicine can dissolve in different types of polyacrylic pressure-sensitive adhesives, disperse in colloids, and form a uniform solution. While colchicine has low solubility / dispersibility in silicone pressure-sensitive adhesive 4302, it exhibits the same solubility in polyacrylic / silicone composite pressure-sensitive adhesive 6302 as in a single polyacrylic pressure-sensitive adhesive. These experimental results demonstrate that colchicine can meet certain solubility and dispersibility requirements in different polyacrylic pressure-sensitive adhesives, silicone pressure-sensitive adhesives, or acrylic / silicone composite pressure-sensitive adhesives.

[0111] The stability (presence or absence of crystallization) of different colchicine contents in pressure-sensitive adhesives (e.g., 4098 pressure-sensitive adhesive) was observed under an optical magnifier for 0 days and 4 months, and the results are shown in Figure 1.

[0112] Figure 1a shows the image at 0 days, indicating that 4098 pressure-sensitive adhesives containing 5% or less colchicine are transparent, while those containing more than 5% are translucent. Figure 1b shows the image after 4 months, indicating that 4098 pressure-sensitive adhesives containing 5% or more colchicine crystallize after 4 months at room temperature. Those containing less than 5% colchicine show no crystals and maintain a clear, good viscosity. These stability results indicate that the highest solubility of colchicine in a typical acrylic pressure-sensitive adhesive is approximately 5% without the addition of a penetration enhancer.

[0113] Examples 2 to 30 The weight percent content of colchicine, pressure-sensitive adhesive, and penetration enhancer in the polymer matrix layers of Examples 2 to 30 is shown in Table 4.

[0114] Table 4. Weight percent content of colchicine, pressure-sensitive adhesive, and penetration enhancer in the polymer matrix layer of Examples 2 to 30 [Table 4-1] [Table 4-2]

[0115] The results in Table 4 show that the addition of different types of penetration enhancers has different effects on the change in penetration efficiency. Non-alcohol penetration enhancers such as menthol, dimethicone, oleic acid, IPP, PEG600, and DMI did not have a significant penetration-enhancing effect on either acrylic or silicone pressure-sensitive adhesives, while alcohols or alcohol derivatives such as DGME, HEP, TEOA, and DPG had a significant penetration-enhancing effect. However, the penetration-enhancing effect is related to the structure of alcohols such as oleyl alcohol and PEG600, which contain alcohol hydroxyls. As the chain length increases, the penetration-enhancing effect is either absent or slight.

[0116] Examples 31 to 44 The components and weight percentages of the contents of the colchicine-containing patches in Examples 31 to 44 are as shown in Table 5.

[0117] Table 5. List of components and weight percentages of the colchicine-containing patches in Examples 31 to 44 [Table 5]

[0118] The results in Table 5 show that backing films with different properties have a significant effect on penetration performance and application performance. Here, 3M Scotchpak™ 9754 (polyester PET), 3M™ CoTran™ 9720 & SHANGHAI YIGKE 3601 (polyethylene PE), 3M Scotchpak™ 9733 (polyester PET / polyvinyl acetate EVA blend), Xiaoshan Elastic Cloth 6015A, Japan Vilene Nonwoven Fabric EW2083, and 3M CoTran™ 9701 (polyurethane, PU) showed a significant decrease in permeability, indicating that non-occlusive backing films have a significant impact on permeation. This is because water produced by skin respiration at the application site can pass through the colloid matrix layer and then the backing layer. When passing through the colloid matrix layer, the excellent water solubility of colchicine increases the solubility of the active ingredient in the colloid matrix, thereby reducing its thermodynamic diffusion rate and further significantly reducing permeation rate. In the case of completely non-occlusive backing films such as elastic fabrics and nonwoven fabrics, peel failures still occur. On the other hand, the aluminum-containing occlusive backing film 3M Scotchpak™ 9738 has good permeation performance because it forms a closed system and water cannot completely pass through the colloidal matrix layer, so the impact on the active ingredient is small and no obvious change in permeation ability is observed.

[0119] Comparative Examples 1 to 12 The weight percentages of the colchicine, pressure-sensitive adhesive, and penetration enhancer content in the polymer matrix layers of Comparative Examples 1 to 12 are shown in Table 6.

[0120] Table 6: Weight percent content of colchicine, pressure-sensitive adhesive, and penetration enhancer in the polymer matrix layer of Comparative Examples 1 to 12 [Table 6]

[0121] The results in Table 6 show that the addition of short-chain branched or straight-chain alcohol penetration enhancers destroys the colloidal properties. This is because the short-chain branched or straight-chain alcohol penetration enhancers have higher polarity, while the silicone-based pressure-sensitive adhesive has very low polarity. Although the penetration enhancers can dissolve colchicine uniformly or disperse it in the pressure-sensitive adhesive system, the compatibility issues between the penetration enhancers and the pressure-sensitive adhesive cause part of the adhesive solution to change from a homogeneous solution to a clumpy, insoluble, jelly-like mixture, making it impossible to apply.

[0122] Preparation of Example 2: The colchicine-containing patch was prepared as follows. Step 1): First, weigh the prescribed dose of colchicine and penetration enhancer, add the same weight of absolute ethanol, and dissolve under stirring. The stirring time depends on the sample amount, usually 15 to 30 minutes, to obtain a mixed solution. Step 2): Weigh out the prescribed amount of polymeric pressure-sensitive adhesive, and while continuing to stir, slowly add dropwise 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 in the ethanol solution, and is usually 5 to 30 minutes. After the addition is complete, continue stirring for 10 to 30 minutes to uniformly disperse the entire adhesive solution matrix, thereby obtaining an adhesive solution. Step 3): The adhesive solution obtained in step 2) is uniformly stirred and applied to a 3M Scotchpak™ 9744 release liner in a thickness that depends on the final clinical use. The applied polymer matrix is passed through an oven with an exhaust function and dried at 35-50°C for 5-15 minutes to remove the organic solvent. The specific drying temperature and time are determined by the application speed and the amount of residual solvent. Step 4): The product obtained in step 3) is laminated with 3M Scotchpak™ 9738 backing film, and finally punched and packaged according to the required specifications to obtain colchicine-containing patches.

[0123] The preparation methods of Examples 3 to 44 are the same as the preparation method of Example 2.

[0124] The preparation methods of Comparative Examples 1 to 12 were the same as the preparation method of Example 2.

[0125] Experimental Example 1: Colchicine solubility experiment Approximately 2 g of colchicine raw material was weighed into a 100 ml brown volumetric flask, 10 ml of solvent was added, and the mixture was mixed uniformly. The flask was then placed in a 25°C water bath oscillator and monitored constantly. Once the solution became clear, the raw material was added continuously. After 24 hours of oscillation in the 25°C water bath oscillator, a precipitate still remained, indicating that the solution was saturated. The saturated solution was centrifuged, and the supernatant was collected and diluted to the appropriate concentration. The concentration was measured using the external standard method, and the solubility was calculated. The results are shown in Table 7.

[0126] Table 7. Solubility of colchicine in different solvents [Table 7]

[0127] The results in Table 7 show that colchicine has the highest solubility in water, followed by alcohols, alcohol ethers, and alcohol amines, and has low solubility in ethyl acetate.

[0128] Experimental example 2: Long-term stability experiment The patch of Example 24 was subjected to a long-term stability test in an environment of 30°C and humidity of 60%±5%RH. The results are shown in Table 8.

[0129] Table 8: Experimental results of the patch of Example 24 in a long-term stability environment [Table 8]

[0130] The results in Table 8 show that the colchicine-containing patch did not produce photodegradation products C and G or other unknown impurities during the stability sample storage period, demonstrating the stability of the transdermal drug delivery system of the present invention.

[0131] Experimental Example 3: In vitro penetration experiment The in vitro percutaneous study of the patch of Example 24 was performed using a Franz vertical diffusion cell. The dorsal skin of a 30-day-old Bama miniature pig was used, with a thickness of 0.3 mm. The receiver solution was a PBS solution at pH 7.4, the receiver cell volume was 7 mL, the temperature setting was 32±0.1°C, and the stirring speed was 200 rpm. 3 mL of samples were collected at 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h, followed by the addition of an isothermal blank receiver solution. Each sample group was prepared in triplicate. Based on the results, the cumulative permeation amount at each time point was calculated, as shown in Figure 2.

[0132] The results in Figure 2 show that water significantly influences the permeation behavior of colchicine-containing patches. Due to the high water solubility of colchicine, water in the receiver medium penetrates the colloidal matrix of the patch, significantly reducing its permeability (see Experimental Example 4, in vivo dorsal permeation data in Bama miniature pigs).

[0133] Experimental Example 4: In vivo penetration experiments in Bama miniature pigs In vivo permeation experiments of the patch of Example 24 investigated the effect of water on permeation. Experimental design: Samples were placed in a high humidity environment of 92.5% RH for 72 hours. One side had a release liner, while the other side had the release liner removed in advance to directly expose the colloid matrix to the high humidity environment. A dorsal percutaneous experiment was conducted on a 30-day-old Bama miniature pig, and the results are shown in Figure 3.

[0134] The results in Figure 3 show that water significantly affects the permeation behavior of colchicine-containing patches. Due to the high water solubility of colchicine, water in the environment significantly affects its permeation behavior. Water absorbed from the environment into the patch inhibits the permeation behavior of colchicine. After the samples were treated in a high-humidity environment, the in vivo permeation of the samples with release liner on the backs of Bama miniature pigs was slightly reduced, while the in vivo permeation of the samples without release liner on the backs of Bama miniature pigs was significantly reduced.

[0135] Experimental Example 5: Local concentration experiment in rat joint capsule Seventy-two male SD rats were randomly divided into six groups based on body weight, consisting of an experimental group and a model control group. The experimental group consisted of low, medium, and high dose groups of Test Formula 1, a Test Formula 2 group, and a colchicine intragastric administration control group. Each experimental group and model control group consisted of 12 rats, and each group was randomly divided into two subgroups, Subgroups 1 and 2, each consisting of six rats. Six non-model rats served as a normal control group. The specific groupings are shown in Table 9. The low, medium, and high dose groups of Test Formula 1 correspond to Examples 29, 28, and 24, respectively. Test Formula 2 group corresponds to Example 18.

[0136] Table 9. List of rat groups [Table 9]

[0137] The low, medium, and high dose groups of Test Formula 1 and Test Formula 2 were administered 4 hours and 28 hours after modeling, respectively, and the corresponding test samples (approximately 0.75 cm 2At the same time as the patch administration, the rats' trunks were restrained with gauze and adhesive tape, and the rats were kept in individual cages to prevent them from biting the patch themselves or each other. If the patch becomes detached during the test, this must be recorded and supplemented.) was attached to the ankle joint. After 12 hours of patch administration, the rats were released from the administration and trunk restraint. The normal control group and the model control group received blank patches for the same period of time and in the same way.

[0138] In the control group, colchicine was administered intragastrically at a dose of 0.25 mg / kg once each at 4, 16, 28, and 40 hours after modeling, with the administration volume being 5 mL / kg.

[0139] Subgroup 1 and subgroup 2 were dissected 19 and 43 hours after modeling, respectively. The normal control group was dissected 43 hours after modeling. The colchicine concentration in the joint capsule tissue was detected after homogenization, and the results are shown in Table 10.

[0140] Table 10. Colchicine concentrations in the joint capsule tissue of rats in each experimental and control group [Table 10]

[0141] The results in Table 10 show that the colchicine concentration in the rat joint capsule after application of the patch was much higher than that in the stomach.

[0142] Experimental Example 6: Irritation experiment using rabbits Four Japanese white rabbits were used for each of the blank control group, low-dose test formula 1 group (Example 29), medium-dose test formula 1 group (Example 28), and high-dose test formula 1 group (Example 24), and each group was administered the treatment at four locations on the back skin of each white rabbit. One to two days before administration, the hair at the administration site was removed using a hair removal device to create a depilated area of approximately 5 x 5 cm square. Depilatory cream was applied to the depilated site so that it could be evenly distributed, and the treatment was continued for approximately 40 to 60 seconds. After that, the depilated site was rinsed with warm water to completely remove the depilatory cream, and the moisture was absorbed with gauze.

[0143] Before administration, the skin at the depilated site was photographed and stored, and a test product measuring 3 cm in diameter was applied to the administration site. After 8 hours, it was removed. After removing the test product, the skin reaction was observed with the naked eye 60 minutes, 24 hours, 48 hours, and 72 hours later, and the degree of irritation and edema was scored according to Table 11.

[0144] Table 11. Scoring criteria for skin irritation reactions [Table 11]

[0145] The average skin reaction score for each group at each time point was calculated, and the irritation intensity was evaluated according to Table 12.

[0146] Table 12. Evaluation criteria for skin irritation intensity [Table 12]

[0147] After administration, an irritation score was assigned to each group of white rabbits. Of these, the blank control group, the low-dose group of test formula 1 (Example 29), the medium-dose group of test formula 1 (Example 28), and the high-dose group of test formula 1 (Example 24) showed no erythema or edema at any time point after administration, and the skin irritation intensity evaluation was 0 points in all cases. This means that when the weight percentage of colchicine content is 0.5%, 1%, or 2%, it can be determined that the colchicine-containing patches are not irritating.

[0148] Experimental Example 7: Study on local tissue distribution of colchicine in Bama miniature pigs Eight Bama miniature pigs (all male) of the same sex were randomly divided into two groups based on body weight, with four pigs per group. The first group, the patch group, received a single transdermal administration of four patches containing colchicine of the present invention prepared in Example 30 to the joints of the limbs per pig (each patch had a size of 5 cm x 7 cm). The second group, the tablet group, received a single oral intragastric administration of two colchicine tablets (purchased from Takada Pharmaceutical Co., Ltd., lot number UX10) per pig (1 mg / pigs).

[0149] Table 13. Administration information by group [Table 13]

[0150] Note: The first digit of the animal number indicates the sex (1 for male, 2 for female), the second digit indicates the group (1 for group 1, 2 for group 2, etc.), and the last two digits indicate the sequential number of the animal.

[0151] One animal per group was dissected 0.5, 2, 4, and 8 h after administration to collect plasma, liver, kidneys, stomach, duodenum, rectum, joint capsules of the limbs (left anterior, right anterior, left posterior, and right posterior), joint skin, and subcutaneous tissue. Tissue samples were weighed, mixed with acetonitrile at a ratio of 1:3 (w:v, g / mL), and homogenized using a high-throughput tissue grinder to prepare Bama miniature pig tissue homogenates.

[0152] The colchicine concentration in each tissue sample of the Bama miniature pig was quantitatively detected by LC-MS / MS method.

[0153] The distribution of Bama miniature butacolchicine in each tissue collected at each time point was statistically analyzed, and pharmacokinetic parameters in each tissue and plasma were calculated.

[0154] result: For the first group of patches, after transdermal administration of the colchicine-containing patch of the present invention to the limb joints of Bama miniature pigs, as shown in Figures 4 to 6, colchicine was distributed mainly in the skin tissue, then in the subcutaneous tissue and joint capsule, with relatively little in the plasma, liver, kidney and digestive tract. The colchicine concentrations in each tissue at different time points were arranged in the following order: The order of exposure for 0.5h was limb skin tissue > limb subcutaneous tissue > limb joint capsule, and plasma, liver, kidney, stomach, duodenum, and rectum were all below the lower limit of quantification. The order of exposure for 2h was limb skin tissue > limb subcutaneous tissue > limb joint capsule > liver > kidney > plasma > duodenum > stomach > rectum. The order of exposure for 4h was limb skin tissue > limb subcutaneous tissue > limb joint capsule > duodenum > plasma > liver > kidney > stomach > rectum. The order of exposure for 8h was limb skin tissue > limb subcutaneous tissue > limb joint capsule > kidney > liver > duodenum > stomach > rectum > plasma. 0-8h ) were in the following order: limb skin tissue > limb subcutaneous tissue > limb joint capsule > liver > duodenum > kidney > plasma > stomach > rectum.

[0155] For the second tablet group, after oral intragastric administration of colchicine tablets to Bama miniature pigs, as shown in Figure 7, colchicine was mainly distributed in the liver, kidneys, and gastrointestinal tract, with relatively little in plasma, skin tissue, subcutaneous tissue, and joint capsules. At 0.5 h, the distribution order was duodenum > stomach > skin tissue of limbs, and plasma, liver, kidney, rectum, joint capsule of limbs, and subcutaneous tissue of limbs were all below the lower limit of quantification. At 2 h, the distribution order was liver > kidney > duodenum > stomach > rectum > skin tissue of limbs > plasma > subcutaneous tissue of limbs > joint capsule of limbs. At 4 h, the distribution order was liver > duodenum > kidney > stomach > rectum > skin tissue of limbs > subcutaneous tissue of limbs > joint capsule of limbs > plasma. At 8 h, the distribution order was liver > kidney > duodenum > stomach > rectum > skin tissue of limbs > subcutaneous tissue of limbs > joint capsule of limbs > plasma. The total exposure (AUC 0-8h ) were duodenum > liver > kidney > stomach > rectum > limb skin tissue > limb subcutaneous tissue > limb joint capsule > plasma.

[0156] Compared with the tablet group, the Bama miniature pig patch group showed a significant decrease in C in the liver, kidney, duodenum, and rectum. max The ratio is 0.02 to 0.22, and the AUC 0-8h The ratios were 0.05 to 0.13, all of which were less than 1. On the other hand, the C of the limb skin tissue, limb subcutaneous tissue, and limb joint capsulemax The ratio was 57.38 to 12866.49, and the AUC 0-8h The ratio was 41.54 to 11019.52.

[0157] Conclusion: After transdermal administration of colchicine-containing patches (11.9 mg / animal) to Bama miniature pigs, colchicine was distributed mainly to the skin tissue, followed by subcutaneous tissue and joint capsules, with relatively little colchicine reaching the plasma, liver, kidneys, and gastrointestinal tract. After oral administration of colchicine tablets (1 mg / animal) to Bama miniature pigs, colchicine was distributed mainly to the liver, kidneys, and gastrointestinal tract, with relatively little colchicine reaching the plasma, skin tissue of the limbs, subcutaneous tissue of the limbs, and joint capsules of the limbs. The patch group showed a significant increase in C in the liver, kidneys, duodenum, and rectum. max and AUC 0-8h All of these were lower than those in the tablet group, and the C max and AUC 0-8h was much higher in the tablet group.

[0158] It should be understood that the above examples are merely illustrative and are not intended to cover all possible embodiments encompassed by the claims. Various modifications and variations can be made based on the above examples without departing from the scope of the present invention. Similarly, various technical features of the above examples can be combined in any manner to form other embodiments of the present invention that may not be explicitly described. Therefore, the above examples merely illustrate some embodiments of the present invention and do not limit the scope of protection of the claims of the present invention. [Industrial Applicability]

[0159] The present invention provides a colchicine-containing patch, its preparation method, and use, which comprises a polymer matrix layer containing the following components by weight: 0.1%-5.0% colchicine, 0.005%-15% permeation enhancer, and 80%-99% pressure-sensitive adhesive. The colchicine-containing patch of the present invention can achieve a therapeutically effective amount through transdermal penetration, causes no local irritation during or after application, is free from gastrointestinal side effects, promotes high patient compliance, and has good economic value and application prospects.

Claims

1. The following ingredients: Colchicine 0.1% to 5.0% 0.005% to 15% penetration enhancer; 80% to 99% pressure-sensitive adhesive; a polymeric matrix layer containing, in weight percent: Preferably, in the polymeric matrix layer, the weight percentage of colchicine is 0.25% to 4.0%, more preferably 0.50% to 3.5%, and even more preferably 0.50% to 3.0%; Preferably, in the polymeric matrix layer, the weight percentage of the penetration enhancer is between 0.01% and 12%, and / or Preferably, the colchicine-containing patch is characterized in that the weight percentage of the pressure-sensitive adhesive in the polymer matrix layer is 85% to 98%.

2. further comprising a backing layer; The colchicine-containing patch according to claim 1, further comprising a protective layer, the polymer matrix layer being positioned between the backing layer and the protective layer.

3. the penetration enhancer is selected from a reagent capable of dissolving colchicine and having a boiling point of 150°C or higher; Preferably, the penetration enhancer is selected from one or more of alcohols, alcohol amines and alcohol ethers; Preferably, the penetration enhancer has a boiling point of 180°C or greater; Preferably, the alcohols are selected from monohydric and / or dihydric alcohols, Preferably, the monohydric alcohol is selected from one or more of lauryl alcohol, oleyl alcohol and terpineol; Preferably, the dihydric alcohol is selected from hexanediol, Preferably, the alcoholamines are selected from one or more of tromethamine, ethanolamine, diethanolamine, triethanolamine, N-hydroxyethylpiperidine, N-hydroxyethylpyrrolidine, N-hydroxyethylpiperazine, N,N-dibutylaminoethanol and N,N-diethylaminoethanol; 3. The colchicine-containing patch according to claim 1, wherein 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.

4. the backing layer is selected from an occlusive backing film or a non-occlusive backing film; Preferably, the backing layer is selected from closed backing films, Preferably, the closed backing film is selected from light-tight closed backing films; Preferably, the occlusive backing film is selected from a polyester / polyethylene composite film backed with metallic aluminum; Preferably, the closed backing film has a thickness of 20 to 100 μm; The colchicine-containing patch according to claim 2, wherein the protective layer is preferably selected from a release liner.

5. 3. The colchicine-containing patch according to claim 1, wherein the pressure-sensitive adhesive is selected from one or more of an acrylic pressure-sensitive adhesive or a silicone pressure-sensitive adhesive, and more preferably, the pressure-sensitive adhesive is selected from one or two of an acrylic pressure-sensitive adhesive or a silicone pressure-sensitive adhesive.

6. The content of colchicine contained in the polymer matrix layer is 10 μg / cm ２ ~150 μg / cm ２ is in the range of Preferably, the administration area of the colchicine-containing patch is 5 cm ２ ~100cm ２ 3. The colchicine-containing patch according to claim 1 or 2, wherein

7. (1) dissolving a prescribed dose of colchicine and a penetration enhancer in an organic solvent to obtain a mixed solution; (2) adding the mixed solution obtained in step (1) dropwise to a prescribed amount of pressure-sensitive adhesive to obtain an adhesive solution; (3) applying the adhesive solution obtained in step (2) to the protective layer and removing the organic solvent; (4) A step of laminating the product obtained in step (3) with a backing layer and punching the resulting product to obtain a colchicine-containing patch.

7. A method for preparing the colchicine-containing patch according to claim 1, comprising:

8. (1') adding a prescribed amount of colchicine, a penetration enhancer, and a pressure-sensitive adhesive to an organic solvent and mixing to obtain an adhesive solution; (2') applying the adhesive solution obtained in step (1') to the protective layer and removing the organic solvent; (3') A step of laminating the product obtained in step (2') with a backing layer and punching the resulting product to obtain a colchicine-containing patch.

7. A method for preparing the colchicine-containing patch according to claim 1, comprising:

9. the organic solvent in step (1) and / or step (1′) is selected from one or more of methanol, ethanol, and isopropanol; The method according to claim 7 or 8, wherein the specific operation of removing the organic solvent in the step (3) and / or the step (2') is to remove the organic solvent by drying under conditions of 35 to 50°C.

10. Use of the colchicine-containing patch according to any one of claims 1 to 6 in the preparation of a medicament for preventing and / or treating gout and / or pericarditis.

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