Transdermal patch containing colchicine and method for its preparation and use

Abstract

The present application relates to a transdermal patch containing colchicine and a preparation method and use thereof. The transdermal patch comprises a matrix layer, wherein the matrix layer comprises an active ingredient colchicine, a hot melt pressure sensitive adhesive and optionally other pharmaceutically acceptable adjuvants, wherein the content of the colchicine is 0.1% to 5%, the content of the hot melt pressure sensitive adhesive is 1.9% to 99.9%, and the content of the other pharmaceutically acceptable adjuvants is 0% to 98% based on the total weight of the matrix layer. The transdermal patch containing colchicine of the present application has no local irritation during and after application, no gastrointestinal side effects, high patient compliance, strong drug permeability, good therapeutic effect, and can be used for preventing and / or treating gout and / or pericarditis.

Description

Technical Field

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

[0002] 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:

[0003]

[0004] 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:

[0005]

[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 cause of 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, and 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 the 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 systems (TDDS) refer to drug delivery methods where drugs are absorbed through the skin or mucous membranes and exert their pharmaceutical effects at the local treatment site or systemically. TDDS offer many advantages, such as no gastrointestinal irritation, avoidance of the first-pass effect in the liver, non-invasiveness, long-lasting release, reduced frequency of dosing, and avoidance of fluctuations in blood drug concentrations associated with oral absorption, 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 transdermal patch containing colchicine that has no local irritation or gastrointestinal side effects during and after application, has strong drug permeability and good therapeutic effect, as well as its preparation method and uses.

[0011] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0012] On one hand, the present invention provides a transdermal patch containing colchicine, comprising a matrix layer containing the active ingredient colchicine, a hot-melt pressure-sensitive adhesive, and optional other pharmaceutically acceptable excipients, wherein, based on the total weight of the matrix layer, the content of colchicine is 0.1% to 5%, the content of the hot-melt pressure-sensitive adhesive is 1.9% to 99.9%, and the content of the other pharmaceutically acceptable excipients is 0% to 98%.

[0013] In a preferred embodiment, the colchicine content, based on the total weight of the matrix layer, is 0.25% to 4.5%, more preferably 0.5% to 4%, and can be more specifically 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, or a percentage within any two of the above values; the hot-melt pressure-sensitive adhesive content is 5% to 95%, preferably 10% to 90%, more preferably 15% to 85%, and can be more specifically 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%. The percentages are 55%, 60%, 65%, 70%, 75%, 80%, 85%, or within any two of the above values; the content of the other pharmaceutically acceptable excipients is 0.005% to 95%, preferably 0.01% to 90%, more preferably 5% to 85%, and may be more specifically 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or within any two of the above values.

[0014] The inventors discovered that colchicine easily causes skin irritation upon contact with skin tissue, and this irritation primarily depends on the colchicine content in the matrix layer, rather than the actual amount of colchicine permeating through the matrix layer into the skin. When the colchicine content in the matrix layer exceeds 5.0%, even with a small amount actually permeating the skin, significant skin irritation can still occur during application. Conversely, when the colchicine content in the matrix layer is less than 5.0%, even a large amount permeates without causing skin irritation. Therefore, controlling the colchicine content in the matrix layer can effectively prevent local irritation from transdermal patches containing colchicine.

[0015] In a preferred embodiment, the hot melt pressure-sensitive adhesive is selected from one or more of polyolefin hot melt adhesives, polyamide hot melt adhesives, polyester hot melt adhesives, and polyurethane hot melt adhesives, and is preferably selected from one or more of styrene-isoprene-styrene block copolymers (SIS), styrene-butadiene-styrene block copolymers (SBS), styrene-ethylene-butene-styrene block copolymers (SEBS), polyisobutylene (PIB), ethylene vinyl acetate, isoprene rubber, and styrene-butadiene rubber (SBR).

[0016] Preferably, the other pharmaceutically acceptable excipients are selected from one or more of the following: penetration enhancers, antioxidants, antiperspirants, absorbents, fillers, thickeners, plasticizers, preservatives, pH adjusters, and surfactants.

[0017] Preferably, the content of the penetration enhancer is 0-30% based on the total weight of the matrix layer, and more specifically, it can be 0%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, or a percentage within any two of the above values; the content of the antioxidant is 0-20%, and more specifically, it can be 0%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, or a percentage within the range defined by any two of the above values; The content of the antiperspirant is 0% to 10%, and may be more specifically 0%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or a percentage within the range defined by any two of the above values; the content of the absorbent is 0% to 40%, and may be more specifically 0%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or a percentage within the range defined by any two of the above values; the content of the absorbent is 0% to 40%, and may be more specifically 0%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or a percentage within the range defined by any two of the above values. %, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, or a percentage within a range defined by any two of the above values; the filler content is 0-50%, and may be more specifically 0%, 0.1%, 0.2%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or a percentage within a range defined by any two of the above values; the tackifier content is 0-6%. 0%, which can be more specifically 0%, 0.1%, 0.2%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or a percentage within a range defined by any two of the above values; the plasticizer content is 0-60%, which can be more specifically 0%, 0.1%, 0.2%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or a percentage within a range defined by any two of the above values; the preservative content is 0-10%, which can be more specifically 0%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or a percentage within the range defined by any two of the above values; the pH adjuster content is 0-20%, and may be more specifically 0%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or a percentage within the range defined by any two of the above values. The percentage within the range; and / or the content of the surfactant is 0% to 30%, which may be more specifically 0%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, or a percentage within the range defined by any two of the above values.

[0018] Preferably, the penetration enhancer is selected from one or more of alcohols, alkanolamines, and alcohol ethers; more preferably, the penetration enhancer is selected from alcohols such as diethanol, hexanediol, terpineol, lauryl alcohol, oleyl alcohol, camphor, borneol, etc.; alcohol ethers such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monohexyl ether, dipropylene glycol methyl ether, dipropylene glycol butyl ether, and dipropylene glycol condensate, etc.; alkanolamines such as tromethamine, ethanolamine, diethanolamine, triethanolamine, N-hydroxyethylpiperidine, N-hydroxyethylpyrrolidine, N-hydroxyethylpiperazine, N,N-dibutylaminoethanol, and N,N-diethylaminoethanol, etc.; and others such as dimethyl sulfoxide, N-methylpyrrolidone, and oleic acid, etc.

[0019] The antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, 2-mercaptobenzimidazole, tocopherol, ascorbic acid, nordihydroguaiaric acid, gallic acid, vitamin E, sodium thiosulfate, and sodium sulfite.

[0020] The antiperspirant is selected from one or more of the following: aluminum hydroxychloride, aluminum dichloride, aluminum sesquichloride, aluminum hydroxychloride PG coordination compound, aluminum hydroxychloride PEG coordination compound, aluminum hydroxychloride zirconium pentachlorohydrin, aluminum hydroxychloride zirconium octachlorohydrin, aluminum hydroxychloride zirconium trichlorohydrin, aluminum hydroxychloride zirconium tetrachlorohydrin PG coordination compound, aluminum hydroxychloride zirconium tetrachlorohydrin GLY coordination compound, aluminum chloride, aluminum ammonium sulfate, aluminum hydroxide, and alum.

[0021] The absorbent is selected from one or more of the following: sugar polymer absorbent, absorbent resin, absorbent silica gel, polyvinyl alcohol, sodium polyacrylate, calcium sulfate, and calcium chloride;

[0022] The filler is selected from one or more of zinc oxide, titanium oxide, calcium carbonate, magnesium carbonate, zinc stearate, kaolin, talc, bentonite, fumed silica, hydrated silica, aluminum silicate, magnesium silicate, magnesium aluminum silicate, and aluminum hydroxide.

[0023] The tackifier is selected from one or more of petroleum resin, phenolic resin, xylene resin, coumarin indene resin, rosin derivatives, alicyclic saturated hydrocarbon resins, aliphatic hydrocarbon resins, aromatic hydrocarbon resins, maleic acid resins, and terpene resins; preferably, the rosin derivative is selected from one or more of rosin, rosin glycerol esters, hydrogenated rosin, hydrogenated rosin glycerol esters, pentaerythritol rosin esters, and rosin resins.

[0024] The plasticizer is selected from one or more of the following: mineral oil, linseed oil, octyl palmitate, squalene, squalane, silicone oil, isobutyl myristate, isostearyl alcohol, oleyl alcohol, liquid paraffin, hydrogenated oil, hydrogenated castor oil, higher alcohols (such as octyldodecyl alcohol), castor oil, petroleum-based oils (such as paraffin-based processed oils, naphthenic-based processed oils, or aromatic-based processed oils), vegetable-based oils (such as olive oil, camellia oil, tall oil, or peanut oil), diesters (such as dibutyl phthalate, dioctyl phthalate), liquid rubbers (such as polybutene, liquid isoprene rubber), liquid fatty acid esters (such as isopropyl myristate, hexyl laurate, diethyl sebacate, or diisopropyl sebacate), diethylene glycol, polyethylene glycol, ethylene glycol salicylate, propylene glycol, glycerol, dipropylene glycol, triacetate, and triethyl citrate.

[0025] The preservative is selected from one or more of methylparaben, ethylparaben, propylparaben, benzyl alcohol, benzalkonium bromide, chlorhexidine acetate, and sodium benzoate.

[0026] The pH adjuster is selected from one or more of inorganic acids, inorganic bases, organic acids, and organic bases; and / or

[0027] The surfactant is selected from one or more of nonionic, anionic, cationic, and amphoteric surfactants.

[0028] Preferably, the transdermal patch of the present invention further comprises a backing layer and a protective layer; the matrix layer is located between the backing layer and the protective layer;

[0029] Preferably, the backing layer is selected from closed backing films;

[0030] Preferably, the closed backing film is selected from light-shielding closed backing films;

[0031] Preferably, the closed backing film is selected from a polyester-polyethylene composite film with a metal aluminum liner;

[0032] Preferably, the thickness of the closed backing film is 20–100 μm, more preferably 20–80 μm;

[0033] Preferably, the protective layer is selected from release film.

[0034] Because colchicine has good water solubility, moisture from skin respiration at the application site can enter the colloidal matrix during application, affecting the solubility of this water-soluble component within the matrix and consequently its thermodynamic diffusion capacity, i.e., its permeability. To address the impact of moisture generated by skin respiration on the patch's permeability during application, this invention preferably uses a closed backing film. The closed backing film ensures good and controllable permeability and maintains good adhesion of the colloidal matrix after application, meeting the wearing requirements during patch use. A light-protecting backing film reduces or eliminates the risk of colchicine decomposition upon exposure to light.

[0035] In some specific implementations, the backing film is selected from ScotchPak of 3M. TM 1109, ScotchPak TM 9738 or ScotchPak TM 9730, preferably ScotchPak TM 9738.

[0036] Preferably, in the transdermal patch of the present invention, the content of colchicine in the matrix layer is in the range of 10 μg / cm³. 2 ~150μg / cm 2 ;

[0037] Preferably, the application area of ​​the patch is 5 cm². 2 ~100cm 2 .

[0038] Preferably, in the transdermal patch of the present invention, the water content in the matrix layer is less than 2% based on the total weight of the matrix layer, more preferably less than 1%, and even more preferably less than 0.5%.

[0039] The inventors unexpectedly discovered that the water content in the matrix layer is closely related to the permeability of colchicine; when the water content in the matrix layer exceeds 2%, the permeability of colchicine decreases significantly. Therefore, the water content in the matrix layer should be controlled to be less than 2%, preferably less than 1%, and more preferably less than 0.5%. A backing layer and protective layer with poor water permeability can be used to prevent the patch from absorbing moisture from the environment during storage and use. Furthermore, water-absorbing agents and desiccants can be added to the formulation to control the water content and prevent the formulation from absorbing moisture from the environment during storage and use, thus affecting its permeability. Antiperspirants can also be added to the matrix layer to prevent excessive sweating during use from increasing the water content in the matrix layer and thus affecting the permeability of colchicine.

[0040] On the other hand, the present invention provides a method for preparing the colchicine-containing transdermal patch of the present invention, comprising the following steps:

[0041] The prescribed amount of colchicine is mixed with a hot-melt pressure-sensitive adhesive and optional other pharmaceutically acceptable excipients. All components are melted and mixed at a temperature of 140–190°C. The mixture is then applied to a backing layer or a protective layer to form a matrix layer. The protective layer or backing layer is then bonded together with the matrix layer sandwiched between the backing layer and the protective layer. Finally, it is cut to the required size to obtain the colchicine-containing transdermal patch.

[0042] In another aspect, the present invention provides the use of the colchicine-containing transdermal patch of the present invention in the preparation of a medicament for the prevention and / or treatment of gout and / or pericarditis.

[0043] The colchicine-containing transdermal patch of the present invention contains a colchicine content sufficient to achieve a therapeutic effect through transdermal penetration, while not causing local skin irritation during or after application, having no gastrointestinal side effects, high patient compliance, strong drug permeability, and good therapeutic effect. It can be used for the prevention and / or treatment of gout and / or pericarditis. Detailed Implementation

[0044] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing 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.

[0045] Unless otherwise stated, all contents mentioned in the context of this invention are by weight.

[0046] In the following embodiments, English abbreviations are shown in Table 1.

[0047] Table 1. English Abbreviations

[0048] Serial Number abbreviation Chinese name / Full model name 1 SIS Styrene-isoprene-styrene block copolymer 2 SBS Styrene-butadiene-styrene block copolymer 3 SEBS Styrene-ethylene-butene-styrene block copolymer 4 PIB Polyisobutylene 5 9738 <![CDATA[3M Scotchpak TM 9738]]> 6 9733 <![CDATA[3M Scotchpak TM 9733]]> 7 9701 <![CDATA[3M CoTran TM 9701]]> 8 9754 <![CDATA[3M Scotchpak TM 9754]]> 9 1109 <![CDATA[3M ScotchPak TM 1109]]> 10 9730 <![CDATA[3M ScotchPak TM 9730]]>

[0049] Example 1 The effect of colchicine content on skin irritation

[0050] The prescribed amounts of colchicine were mixed with hot-melt pressure-sensitive adhesive according to the contents shown in Table 2, and melted and mixed at a temperature of 140–190°C. The mixture was then coated onto a backing layer to form a matrix layer. The protective layer was then laminated with the matrix layer sandwiched between the backing layer and the protective layer. The patch was cut to the required size to obtain a transdermal patch containing colchicine. Skin irritation was measured 6 and 12 hours after application.

[0051] Table 2. Effects of colchicine content on skin irritation.

[0052]

[0053] The results in Table 2 show that the colchicine content in the patch directly affects its skin irritation. When the content is greater than 5%, skin irritation is likely to occur 6–12 hours after application. Controlling the colchicine content in the formulation to less than 5% can effectively avoid skin irritation.

[0054] Example 2 Preparation and permeability study of the patch

[0055] The colchicine-containing transdermal patch was prepared according to the prescription shown in Table 3 below, and the preparation method is as follows:

[0056] The prescribed amount of colchicine is mixed with a hot-melt pressure-sensitive adhesive and other pharmaceutically acceptable excipients (such as tackifiers, plasticizers, penetration enhancers, absorbents, and / or antiperspirants). All components are melted and mixed at a temperature of 140–190°C. The mixture is then applied to a backing layer to form a matrix layer. The protective layer is then bonded together with the matrix layer sandwiched between the backing layer and the protective layer. The patch is then cut to the required size to obtain a transdermal patch containing colchicine.

[0057] Table 3. Formulation composition and permeability of transdermal patches containing colchicine.

[0058]

[0059]

[0060] As can be seen from the results in Table 3, different backing membrane properties significantly affect permeability. Among them, the non-closed backing membrane 3M Scotchpak...TM 9754 (PET), 3M Scotchpak TM 9733 (a blend of polyester PET and polyvinyl acetate EVA film) and 3M CoTran TM 9701 (polyurethane, PU) significantly reduces permeability, indicating that a non-closed backing film severely affects permeability. This may be because moisture generated by skin respiration at the application site passes through the colloidal matrix layer and then through the backing layer. During this passage through the colloidal matrix layer, the excellent water solubility of colchicine increases the solubility of the active ingredient, thus reducing its thermodynamic diffusion capacity and consequently resulting in a significant decrease in permeability. In contrast, 3M Scotchpak, which contains a closed backing film... TM 9738, 3M ScotchPak TM 1109, 3M ScotchPak TM The 9730 patch has good permeability, possibly because it forms a closed system, preventing water from completely passing through the colloidal matrix layer, thus having a smaller impact on the active ingredients and showing no significant change in permeability.

[0061] Studies have shown that the moisture content in the matrix layer significantly affects the permeation behavior of colchicine. Due to the high water solubility of colchicine, moisture absorbed by the patch from the environment inhibits its permeation. When the moisture content in the matrix layer exceeds 2%, the permeation capacity of colchicine decreases significantly. Therefore, this invention preferably controls the moisture content in the matrix layer to be less than 2%, more preferably less than 1%, and even more preferably less than 0.5%.

[0062] A backing layer and protective layer with poor water permeability can be used to prevent the patch from absorbing moisture from the environment during storage and use. In addition, water-absorbing agents and desiccants can be added to the formulation to control its water content and prevent it from absorbing moisture from the environment during storage and use, thus affecting its permeability. Antiperspirants can also be added to the matrix layer to prevent excessive sweating during use from increasing the water content in the matrix layer and thus affecting the permeability of colchicine.

[0063] Example 3 Pharmacodynamic studies of a rat model of acute gout arthritis

[0064] Five blank control animals were randomly selected from 26 healthy male SD rats (weighing 240±10g). 0.2mL of 0.9% saline was injected into the right ankle joint cavity of each rat in the blank control group using a 1mL syringe. All other rats were injected into the right ankle joint cavity with 0.2mL of sodium urate suspension (20mg / mL). Two hours after modeling, unqualified model animals were removed, and all remaining model animals were randomly divided into three groups: a model control group, a positive drug (colchicine tablets, purchased from Takada Pharmaceutical Co., Ltd.) group, and a test sample group (sample numbered 9 in Example 2 of this invention), with five rats in each group.

[0065] The day after animal modeling, the blank control group was given pure water by gavage, while the model control group was given blank drug patches. The clinically recommended adult dose of colchicine in the positive control group was 3-4 mg / day. Based on the equivalent dose ratio calculated using human and animal body surface area in "Pharmacological Experimental Methodology," the rat dose was approximately 0.36 mg / kg, administered via gavage via a rat gavage syringe. In the test sample group, the rats received two 1cm × 2cm patches (approximately 1.36 mg / kg) applied to their ankle joints for 4 hours. All groups received the drug once daily for 7 consecutive days. Serum concentrations of inflammatory factors IL-6 and IL-1β were measured 4 hours after administration, and the ankle circumference was measured to calculate the swelling inhibition rate. The results are shown in Tables 4-6 below.

[0066] Table 4. Measurement results of inflammatory factor IL-6 concentration

[0067]

[0068] Table 5. Measurement results of inflammatory factor IL-1β concentration.

[0069]

[0070] As can be seen from the results in Tables 4-5, compared with the model control group, the test sample group of the present invention had the highest inhibition rate of IL-6 inflammatory factor in rat serum (approximately 83%) and the highest inhibition rate of IL-1β inflammatory factor in rat serum (approximately 90%).

[0071] Table 6 Results of the swelling inhibition rate study

[0072]

[0073] As can be seen from the results in Table 6, compared with the model control group (given a blank patch), the swelling inhibition rate of the test sample group of the present invention was approximately 62% to 85%, which was significantly higher than the swelling inhibition rate of the positive drug group (up to approximately 53%).

[0074] On the third day of administration, it was found that all four rats in the positive control group (out of a total of five) had varying degrees of loose stools, which may be related to the gastrointestinal irritation caused by oral colchicine. No rats in the test sample group had loose stools.

[0075] After administration on day 7, pathological examination revealed no significant sodium urate crystals in the ankle joint capsules of animals in the test sample group, a small amount of sodium urate crystals in the ankle joint capsules of animals in the positive control group, and a large amount of sodium urate crystals in the ankle joint capsules of animals in the model control group (blank control patch). This indicates that administration of the test sample of this invention resulted in a more significant reduction in sodium urate crystals within the joint capsules of the animals, which may be related to the reduction of inflammatory symptoms.

Claims

1. A transdermal patch containing colchicine, comprising a matrix layer, a backing layer, and a protective layer, wherein the matrix layer is located between the backing layer and the protective layer, and the matrix layer comprises the active ingredient colchicine, a hot-melt pressure-sensitive adhesive, a tackifier, a plasticizer, a penetration enhancer, and optionally other pharmaceutically acceptable excipients. Based on the total weight of the matrix layer, the content of colchicine is 1.5% to 5%, the content of the hot-melt pressure-sensitive adhesive is 30% to 50%, the content of the tackifier is 25% to 35%, the content of the plasticizer is 20% to 35%, the content of the penetration enhancer is 0.1% to 20%, and the content of other pharmaceutically acceptable excipients is 0% to 20%. The hot melt pressure-sensitive adhesive is selected from one or more of styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-ethylene-butene-styrene block copolymer, polyisobutylene, ethylene vinyl acetate, isoprene rubber and styrene-butadiene rubber; The tackifier is selected from one or more of the following: phenolic resin, xylene resin, rosin, rosin glycerol ester, hydrogenated rosin, hydrogenated rosin glycerol ester, pentaerythritol rosin ester, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, aromatic hydrocarbon resin, maleic acid resin, and terpene resin. The plasticizer is selected from one or more of the following: mineral oil, linseed oil, octyl palmitate, squalene, squalane, isobutyl myristate, isostearyl alcohol, oleyl alcohol, hydrogenated castor oil, octyl dodecyl alcohol, castor oil, olive oil, camellia oil, peanut oil, dibutyl phthalate, dioctyl phthalate, polybutene, isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate, diethylene glycol, polyethylene glycol, propylene glycol, glycerol, dipropylene glycol, triacetate, and triethyl citrate. The backing layer is selected from closed backing films, wherein the closed backing films are selected from 3M Scotchpak™ 9738, 3M Scotchpak™ 1109 and 3M ScotchPak. TM 9730.

2. The transdermal patch according to claim 1, wherein the other pharmaceutically acceptable excipients are selected from one or more of antioxidants, antiperspirants, absorbents, fillers, preservatives, pH adjusters, and surfactants.

3. The transdermal patch according to claim 2, wherein, Based on the total weight of the matrix layer, the content of the antioxidant is 0-20%, the content of the antiperspirant is 0-10%, the content of the absorbent is 0-20%, the content of the filler is 0-20%, the content of the preservative is 0-10%, the content of the pH adjuster is 0-20%, and / or the content of the surfactant is 0-20%.

4. The transdermal patch according to claim 1, wherein: The penetration enhancer is selected from one or more alcohols, alcohol amines, and alcohol ethers; and / or The plasticizer is liquid paraffin.

5. The transdermal patch according to claim 1, wherein, The penetration enhancer is selected from one or more of diethanol, hexanediol, terpineol, lauryl alcohol, oleyl alcohol, camphor, borneol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monohexyl ether, dipropylene glycol methyl ether, dipropylene glycol butyl ether, dipropylene glycol monomethyl ether, glycerol, ethanolamine, diethanolamine, triethanolamine, N-hydroxyethylpiperidine, N-hydroxyethylpyrrolidine, N-hydroxyethylpiperazine, N,N-dibutylaminoethanol, N,N-diethylaminoethanol, dimethyl sulfoxide, N-methylpyrrolidone, and oleic acid.

6. The transdermal patch according to claim 2 or 3, wherein: The antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, 2-mercaptobenzimidazole, tocopherol, ascorbic acid, nordihydroguaiac acid, gallic acid, sodium thiosulfate and sodium sulfite; The antiperspirant is selected from one or more of the following: aluminum hydroxychloride, aluminum dichloride, aluminum sesquichloride, aluminum hydroxychloride PG coordination compound, aluminum hydroxychloride PEG coordination compound, aluminum hydroxychloride zirconium pentachlorohydrin, aluminum hydroxychloride zirconium octachlorohydrin, aluminum hydroxychloride zirconium trichlorohydrin, aluminum hydroxychloride zirconium tetrachlorohydrin PG coordination compound, aluminum hydroxychloride zirconium tetrachlorohydrin GLY coordination compound, aluminum chloride, aluminum ammonium sulfate, aluminum hydroxide, and alum. The absorbent is selected from one or more of the following: sugar polymer absorbent, absorbent silica gel, calcium sulfate, and calcium chloride; The filler is selected from one or more of zinc oxide, titanium oxide, calcium carbonate, magnesium carbonate, zinc stearate, kaolin, talc, bentonite, fumed silica, hydrated silica, aluminum silicate, magnesium silicate, magnesium aluminum silicate, and aluminum hydroxide. The preservative is selected from one or more of methylparaben, ethylparaben, propylparaben, benzyl alcohol, benzalkonium bromide, chlorhexidine acetate, and sodium benzoate. The pH adjuster is selected from one or more of inorganic acids, inorganic bases, organic acids, and organic bases; and / or The surfactant is selected from one or more of nonionic, anionic, cationic, and amphoteric surfactants.

7. The transdermal patch according to claim 2 or 3, wherein: The absorbent is selected from one or more of polyvinyl alcohol and sodium polyacrylate.

8. The transdermal patch according to claim 1 or 2, wherein, The protective layer is selected from release film.

9. The transdermal patch according to claim 1 or 2, wherein the colchicine content in the matrix layer is in the range of 10 μg / cm³. 2 ~150μg / cm 2 .

10. The transdermal patch according to claim 1 or 2, wherein the patch has a drug delivery area of ​​5 cm². 2 ~100cm 2 .

11. The transdermal patch according to claim 1 or 2, wherein the water content in the matrix layer is less than 2% based on the total weight of the matrix layer.

12. The transdermal patch according to claim 1 or 2, wherein the water content in the matrix layer is less than 1% based on the total weight of the matrix layer.

13. The transdermal patch according to claim 1 or 2, wherein the water content in the matrix layer is less than 0.5% based on the total weight of the matrix layer.

14. A method for preparing a transdermal patch containing colchicine according to any one of claims 1 to 13, comprising the following steps: The prescribed amount of colchicine is mixed with a hot-melt pressure-sensitive adhesive, a tackifier, a plasticizer, a penetration enhancer, and other optional pharmaceutically acceptable excipients. All components are melted and mixed at a temperature of 140–190°C. The mixture is then applied to a backing layer or a protective layer to form a matrix layer. The protective layer or backing layer is then bonded together with the matrix layer sandwiched between the backing layer and the protective layer. Finally, the patch is cut to the required size to obtain the colchicine-containing transdermal patch.

15. The use of a colchicine-containing transdermal patch as described in any one of claims 1 to 13 in the preparation of a medicament for the prevention and / or treatment of gout and / or pericarditis.

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