WO2024067722A1 - 含有秋水仙碱的贴剂及其制备方法和应用 - Google Patents

含有秋水仙碱的贴剂及其制备方法和应用 Download PDF

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Publication number
WO2024067722A1
WO2024067722A1 PCT/CN2023/122148 CN2023122148W WO2024067722A1 WO 2024067722 A1 WO2024067722 A1 WO 2024067722A1 CN 2023122148 W CN2023122148 W CN 2023122148W WO 2024067722 A1 WO2024067722 A1 WO 2024067722A1
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Prior art keywords
colchicine
patch
pressure
sensitive adhesive
polymer matrix
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PCT/CN2023/122148
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English (en)
French (fr)
Inventor
谢文委
律嵩
孙丽娜
王媛
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北京德默高科医药技术有限公司
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Publication of WO2024067722A1 publication Critical patent/WO2024067722A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention belongs to the technical field of transdermal drug delivery, and in particular relates to a patch containing colchicine and a preparation method and application thereof.
  • Colchicine whose chemical name is N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[ ⁇ ]cycloheptatrien-7-yl)-(S)-acetamide, has a molecular formula of C 22 H 25 NO 6 and a molecular weight of 399.4. It is a pale yellow to pale yellowish green amorphous or crystalline powder, odorless, and its color darkens when exposed to light. Its chemical structure is as follows:
  • Colchicine has a special tricyclic structure and is unstable under high temperature and light conditions, especially under light, it produces genotoxic impurities C and G.
  • the chemical structures of impurities C and G are as follows:
  • Colchicine is a natural plant alkaloid that has been used by humans since BC. The first pure product was extracted from the Colchicum plant in 1820. Colchicine is currently 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 largest metabolic disease after diabetes, and colchicine is currently the first-line treatment and prevention drug for acute attacks of gout. In addition to gout, colchicine is also used to treat other diseases such as Mediterranean fever, treatment and prevention of cardiovascular diseases such as pericarditis, and skin diseases such as Sweet's syndrome and psoriasis.
  • diseases such as Mediterranean fever, treatment and prevention of cardiovascular diseases such as pericarditis, and skin diseases such as Sweet's syndrome and psoriasis.
  • colchicine has a small treatment safety window due to the closeness between the therapeutic dose and the toxic dose; at the same time, due to the first-pass effect in the liver, the bioavailability is low.
  • approved oral colchicine all have serious side effects, such as abdominal pain, nausea, vomiting, diarrhea, bone marrow suppression, arrhythmia, and azoospermia. Therefore, although colchicine has high clinical effectiveness, these serious side effects cause more than 80% of patients to be unable to adhere to oral colchicine treatment.
  • Transdermal drug delivery system mainly refers to a drug delivery method in which the drug is absorbed through the skin or mucous membrane and exerts its pharmaceutical effect in the local treatment area or the whole body.
  • Transdermal drug delivery has many advantages, such as no gastrointestinal irritation, avoidance of the first-pass effect of the liver, non-invasiveness, long-term sustained release, the ability to reduce the number of frequent medications, and avoid the fluctuation of blood drug concentration caused by oral absorption, thus having higher safety and good patient compliance.
  • the technical problem to be solved by the present invention is to overcome the deficiencies in the prior art, and provide a patch containing colchicine and a preparation method and application thereof, wherein the patch comprises a polymer matrix layer, and the polymer matrix layer comprises the following components by weight percentage: 0.1% to 5.0% of colchicine; 0.005% to 15% of a permeation enhancer; and 80% to 99% of a pressure-sensitive adhesive.
  • the patch containing colchicine of the present invention can achieve a therapeutic effect through skin penetration, has no local irritation during and after application, has no gastrointestinal side effects, and has high patient compliance.
  • the present invention adopts the following technical solutions:
  • the present invention provides a patch containing colchicine, comprising a polymer matrix layer, wherein the polymer matrix layer comprises the following components by weight percentage:
  • the weight percentage of colchicine in the polymer matrix layer is 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%.
  • the weight percentage of the permeation enhancer in the polymer matrix layer is 0.01% to 12%, and can be specifically 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.50%, 0.70%, 1.00%, 1.50%, 2.00%, 3.00%, 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, or 10.00%.
  • the weight percentage of the pressure-sensitive adhesive in the polymer matrix layer is 85% to 98%, specifically 85%, 90%, 95%, or 98%.
  • the colchicine-containing patch further comprises a backing layer
  • the patch containing colchicine further comprises a protective layer, and the polymer matrix layer is located between the backing layer and the protective layer.
  • the penetration enhancer is selected from agents that can dissolve colchicine and have a boiling point greater than or equal to 150°C;
  • the penetration enhancer is selected from one or more of alcohols, alcohol amines and alcohol ethers;
  • the boiling point of the penetration enhancer is greater than or equal to 180°C;
  • the alcohol is selected from monohydric alcohols and/or dihydric alcohols;
  • the monohydric alcohol is selected from one or more of lauryl alcohol, oleyl alcohol and terpineol;
  • the diol is selected from hexylene glycol
  • the alcoholamine is selected from one or more of tromethamine, ethanolamine, diethanolamine, triethanolamine, N-hydroxyethylpiperidine, N-hydroxyethylpyrrolidine, N-hydroxyethylpiperazine, N,N-dibutylaminoethanol and N,N-diethylaminoethanol;
  • the alcohol ethers are selected from diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol mono One or more of dipropylene glycol ether, dipropylene glycol methyl ether, dipropylene glycol butyl ether and dipropylene glycol.
  • the backing layer is selected from an occlusive backing film or a non-occlusive backing film;
  • the backing layer is selected from occlusive backing films
  • the occlusive backing film is selected from light-shielding occlusive backing films
  • the closed backing film is selected from a polyester polyethylene composite film with a metal aluminum liner;
  • the thickness of the closed backing film is 20 to 100 ⁇ m;
  • the protective layer is selected from a release film.
  • the pressure-sensitive adhesive is selected from one or more of acrylic pressure-sensitive adhesives or silicone pressure-sensitive adhesives; more preferably, the pressure-sensitive adhesive is selected from one or both of acrylic pressure-sensitive adhesives or silicone pressure-sensitive adhesives.
  • the content of colchicine contained in the polymer matrix layer ranges from 10 ⁇ g/cm 2 to 150 ⁇ g/cm 2 ;
  • the administration area of the patch containing colchicine is 5 cm 2 to 100 cm 2 .
  • the present invention provides a method for preparing a patch containing colchicine as described in the present invention, comprising the following steps:
  • step (2) adding the mixed solution obtained in step (1) dropwise to a prescribed amount of a pressure-sensitive adhesive to obtain an adhesive solution;
  • step (3) coating the glue obtained in step (2) on the protective layer and removing the organic solvent;
  • step (3) Compounding the product obtained in step (3) with a backing layer, and punching out to obtain a patch containing colchicine.
  • the present invention provides a method for preparing a patch containing colchicine as described in the present invention, comprising the following steps:
  • step (3') Compounding the product obtained in step (2') with a backing layer, and punching out to obtain a patch containing colchicine.
  • the organic solvent in step (1) and/or (1') is selected from one or more of methanol, ethanol or isopropanol;
  • the specific operation of removing the organic solvent in step (3) and/or (2') is: drying at 35-50°C to remove the organic solvent.
  • the present invention provides use of the colchicine-containing patch of the present invention in the preparation of a medicament for preventing and/or treating gout and/or pericarditis.
  • the present invention also provides a method for treating gout and/or pericarditis, comprising administering a therapeutically effective amount of the patch containing colchicine according to the present invention to a subject in need thereof.
  • the present invention also provides a patch containing colchicine as described in the present invention, which is used for preventing and/or treating gout and/or pericarditis.
  • the present invention has the following advantages compared with the prior art:
  • the colchicine content in the colchicine patch of the present invention can reach a therapeutic effect through skin penetration, and will not cause local skin irritation during and after application, and has no gastrointestinal side effects, and has high patient compliance;
  • the penetration enhancer of the present invention can promote the continuous and controllable percutaneous penetration of colchicine to achieve the therapeutic effect, and has good compatibility with the colloid matrix;
  • the colchicine-containing patch of the present invention comprises a backing layer directly connected to the polymer matrix layer, and the backing layer plays a role in protecting the polymer matrix layer from contact with the surrounding environment and preventing drug loss during use;
  • the backing layer of the present invention is preferably a closed light-proof backing film.
  • the closed backing film has good controllable permeability, and the colloidal matrix remains in a good state after application, thereby maintaining good coating performance, meeting the wearing requirements during the use of the patch.
  • the light-proof backing film reduces or eliminates the risk of preventing colchicine from decomposing in the presence of light.
  • Figure 1a is a state diagram of different contents of colchicine dissolved in 4098 pressure-sensitive adhesive at zero day;
  • FIG1b is a state diagram of colchicine with different contents in 4098 pressure-sensitive adhesive after being placed at room temperature for 4 months;
  • FIG2 is a graph showing the in vitro permeation test results of the patch of Example 24;
  • Fig. 3 is a graph showing the results of an in vivo permeation test of the patch of Example 24;
  • FIG4 shows the concentrations in various tissues or plasma of male Bama miniature pigs after a single transdermal administration of the patch containing colchicine of the present invention at a dose of 11.9 mg/pig;
  • FIG5 and FIG6 are respectively partial enlarged views of FIG4;
  • FIG. 7 shows the concentrations of colchicine in various tissues or plasma after a single oral administration of 1 mg/pig to male Bama miniature pigs.
  • the present invention specifically provides a patch containing colchicine, comprising a polymer matrix layer, wherein the polymer matrix layer comprises the following components by weight percentage:
  • Colchicine has certain skin irritation, and this irritation is related to the composition of the colloidal matrix, including but not limited to the type and content of the penetration enhancer, the type and composition of the pressure-sensitive adhesive, and is directly related to the content of colchicine. Therefore, in order to reduce or eliminate the local skin irritation of the patch containing colchicine at the application site under the premise of ensuring the penetration of the therapeutic amount, in some specific embodiments, the weight of colchicine accounts for 0.1% to 5.0% of the dry weight ratio of the polymer matrix layer, preferably 0.25% to 4.0%, more preferably 0.50% to 3.5%, more preferably 0.50% to 3.0%, and can be more specifically 0.50%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%. Under the above content, it can be ensured that the patch containing colchicine can continuously and controllably deliver the amount to achieve the therapeutic effect during the application period, while reducing or eliminating the local irritation of the skin.
  • the present invention contains a permeation enhancer. Not all types of permeation enhancers can achieve the purpose of the present invention. This is because colchicine has excellent water solubility due to its special structure. It is generally soluble in alcohols and their derivatives, but difficult to dissolve in solvents with low polarity such as ethyl acetate.
  • the pressure-sensitive adhesive system used in the present invention is mainly based on ethyl acetate solvent. Therefore, one problem to be solved by the present invention is to select a suitable permeation enhancer to promote the permeation of colchicine.
  • the skin can penetrate to achieve a therapeutic dose, and colchicine can be uniformly dissolved or dispersed in a colloid matrix containing ethyl acetate as the main solvent system.
  • the penetration enhancer includes but is not limited to alcohols such as methanol, ethanol, diethanol, pineneol, oleyl alcohol, camphor, borneol, etc., alcohol ethers such as diethylene glycol monomethyl ether, etc., alcohol amines such as triethanolamine, N-hydroxyethyl pyrrolidine, etc., and others such as dimethyl sulfoxide (DMSO), N-methylpyrrolidone and oleic acid.
  • alcohols such as methanol, ethanol, diethanol, pineneol, oleyl alcohol, camphor, borneol, etc.
  • alcohol ethers such as diethylene glycol monomethyl ether, etc.
  • alcohol amines such as triethanolamine, N-hydroxyethyl pyrrolidine, etc.
  • others such as dimethyl sulfoxide (DMSO), N-methylpyrrolidone and oleic acid.
  • the present invention unexpectedly found that in a transdermal drug delivery system, while some penetration enhancers have a penetration-enhancing effect, there is a risk of potentially destroying the colloidal properties of the pressure-sensitive adhesive, especially when added at a higher content.
  • the pressure-sensitive adhesive in a solution state is partially converted into a gel state or partially becomes a block, thereby changing the rheological properties of the colloidal state, further leading to coating failure; in some special embodiments, as the content of the penetration enhancer increases, the colloidal properties will be further destroyed. Therefore, the present invention selects a penetration enhancer based on considering both the penetration-enhancing effect and the colloidal properties.
  • the present invention finds that certain types of penetration enhancers have good compatibility with the colloidal matrix and can achieve the expected effect of increasing the diffusion rate.
  • the penetration enhancer is selected from agents that can dissolve colchicine and have a boiling point greater than or equal to 150°C.
  • the penetration enhancer is selected from one or more of alcohols, alcohol amines and alcohol ethers.
  • the boiling point of the penetration enhancer is greater than or equal to 180°C.
  • the alcohol is selected from monohydric alcohols and/or dihydric alcohols.
  • monohydric alcohols include but are not limited to lauryl alcohol, oleyl alcohol and pinene alcohol
  • 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 and N,N-diethylaminoethanol
  • alcohol ethers include but are not limited to diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monohexyl ether, dipropylene glycol methyl ether, dipropylene glycol butyl ether and dipropylene glycol, etc.
  • the penetration enhancers can be used alone or in combination.
  • the penetration enhancer not only has a penetration enhancing effect on colchicine, but also the monohydric alcohol, dihydric alcohol, alcohol amine or alcohol ether penetration enhancer has the ability to increase the dissolution of colchicine in the colloidal matrix, so after the penetration enhancer is added, the solubility of colchicine in the colloidal matrix tends to increase. Another aspect of the increased solubility is that the colchicine at the same content is farther away from reaching or approaching its maximum saturated solubility.
  • the thermodynamic passive diffusion capacity of colchicine is directly related to the degree of approaching saturated solubility, and generally has the highest thermodynamic passive diffusion capacity when reaching or approaching the maximum saturated solubility. Therefore, the addition of a solubilizing penetration enhancer increases the solubility of the colloidal matrix to colchicine, thereby reducing its passive thermodynamic diffusion capacity to a certain extent.
  • the penetration-promoting ability is not only relevant to the penetration-promoting agent type, but also relevant to the content of the penetration-promoting agent. Therefore, the addition of the penetration-promoting agent in some special embodiments reduces the penetration-promoting ability on the contrary, and does not play the penetration-promoting effect.
  • the weight of the permeation enhancer accounts for 0.005% to 15% of the dry weight ratio of the polymer matrix layer, preferably 0.01% to 12%, and can be specifically 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.50%, 0.70%, 1.00%, 1.50%, 2.00%, 3.00%, 5.00%, 6.00%, 7.00%, 8.00%, 9.00%, and 10.00%.
  • the pressure-sensitive adhesive is selected from a pressure-sensitive adhesive pharmaceutically suitable for a transdermal drug delivery system. In some specific embodiments, it is selected from an acrylic pressure-sensitive adhesive based on an acrylic polymer compound or a silicone pressure-sensitive adhesive based on a silicone polymer compound.
  • the acrylic pressure-sensitive adhesive can be any homopolymer, copolymer, terpolymer and polymer of different acrylic acids. Depending on the functional groups contained, it can be a non-functionalized acrylic pressure-sensitive adhesive and a functionalized acrylic pressure-sensitive adhesive, including but not limited to functional groups such as hydroxyl, carboxyl, or both hydroxyl and carboxyl, amino and epoxy. In some embodiments, based on the amount of colchicine active ingredient added and the amount to be delivered to achieve the therapeutic effect, the type and amount of acrylic pressure-sensitive adhesive are also different, and a functionalized acrylic pressure-sensitive adhesive can be selected. Non-functional acrylic pressure sensitive adhesive, or a mixture of the two.
  • the weight of the acrylic pressure-sensitive adhesive accounts for 80% to 99% of the dry weight of the polymer matrix layer, preferably 85% to 98%, specifically 85%, 90%, 95%, or 98%.
  • acrylic pressure-sensitive adhesives include Henkel's Duro-Tak products, such as Duro-Tak 87-900A, Duro-Tak 87-9301 (non-crosslinked, non-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 functional groups), Duro-Tak 87-2852 (crosslinked acrylic pressure-sensitive adhesive, with carboxyl functional groups), Duro-Tak 87-2196 (crosslinked acrylic pressure-sensitive adhesive, with carboxyl functional groups), Duro-Tak 87-2296 (cross-linked acrylic pressure sensitive adhesive with carboxyl functional groups), Duro-Tak 87-2194 (cross-linked acrylic pressure sensitive adhesive with carboxyl functional groups), Duro-Tak 87-2516 (cross-linked acrylic pressure sensitive adhesive with carboxyl functional groups), Duro-Tak
  • the weight of the silicone pressure-sensitive adhesive accounts for 90% to 99% of the dry weight of the polymer matrix layer, preferably 95% to 99%, specifically 95%, 96%, 97%, 98%, 99%.
  • silicone pressure-sensitive adhesives include products from DuPont, such as Liveo TM 7-6102 SilAc Hybrid PSA, Liveo TM 7-6302 SilAc Hybrid PSA, Liveo TM BIO-PSA 7-4502, Liveo TM BIO-PSA 7-4602, Liveo TM BIO-PSA 7-4302 and LiveoTM BIO -PSA 7-4102.
  • the pressure-sensitive adhesive can be selected from a mixture of acrylic pressure-sensitive adhesives and silicone pressure-sensitive adhesives.
  • acrylic pressure-sensitive adhesives and silicone pressure-sensitive adhesives are mixed for use, the colchicine permeability and safety aspects can be determined.
  • the mixing ratio of the two can be adjusted by comprehensive consideration.
  • the mixing method of acrylic pressure-sensitive adhesive and silicone pressure-sensitive adhesive can be physical mixing, that is, mixing two pressure-sensitive adhesives of different properties and stirring them into a uniformly dispersed suspension; acrylic and silicone mixed pressure-sensitive adhesive can also be obtained by chemical synthesis.
  • the dry weight ratio of the pressure-sensitive adhesive composed of a mixture of acrylic pressure-sensitive adhesive and silicone pressure-sensitive adhesive in the polymer matrix layer is 90% to 99%, preferably 95% to 99%, specifically 95%, 96%, 97%, 98%, 99%, and the dry adhesive weight ratio of the acrylic pressure-sensitive adhesive to the silicone pressure-sensitive adhesive can be 30 to 70:70 to 30, specifically 50:50, 40:60, 60:40, 30:70 or 70:30.
  • the patch containing colchicine further includes a backing layer and a protective layer, and the polymer matrix layer is located between the backing layer and the protective layer.
  • the backing layer is directly connected to one surface of the polymer matrix layer. When in use, the backing layer protects the polymer matrix layer from contact with the surrounding environment and prevents drug loss.
  • the protective layer is selected from a release film and is directly connected to the other surface of the polymer matrix layer.
  • the release film is removed before the patch is used.
  • the backing layer is selected from pharmaceutically acceptable backing films, including but not limited to polyester, polyester and vinyl acetate composite film, polyethylene and ethyl acetate composite film, polyurethane, metal foil such as polyester polyethylene composite film with metal aluminum lining, non-woven fabric, stretch fabric, etc.
  • pharmaceutically acceptable backing films including but not limited to polyester, polyester and vinyl acetate composite film, polyethylene and ethyl acetate composite film, polyurethane, metal foil such as polyester polyethylene composite film with metal aluminum lining, non-woven fabric, stretch fabric, etc.
  • colchicine Since colchicine has good water solubility, during the application period, the moisture breathed by the skin at the application site enters into the colloidal matrix, thereby affecting the solubility of such water-soluble components in the colloidal matrix, and further affecting its thermodynamic diffusion capacity, that is, the permeability and coating performance. The extent of the influence depends on the application time and the properties of the backing film.
  • the backing layer is selected from a closed backing film or a non-closed backing film.
  • Closed backing films and non-closed backing films are divided according to their permeability to water and oxygen.
  • Non-closed backing films have a certain degree of permeability to oxygen and water breathed by the skin, such as non-woven fabrics and Elastic fabric has the highest relative moisture and oxygen permeability; closed backing film has a blocking effect on oxygen and moisture of skin respiration, such as polyester polyethylene composite film with metal aluminum lining has extremely low moisture and oxygen permeability.
  • the moisture and oxygen permeation rate can be adjusted according to the properties and thickness of the backing film material.
  • the backing layer is selected from a non-occlusive backing film, which facilitates the discharge of moisture and reduces the decline in the thermodynamic permeability of colchicine, thereby maintaining the permeability.
  • a non-occlusive backing film which facilitates the discharge of moisture and reduces the decline in the thermodynamic permeability of colchicine, thereby maintaining the permeability.
  • part of the colloidal matrix will remain on the skin, resulting in peeling failure.
  • the backing layer is selected from a closed backing film, which has good controllable permeability and the colloid matrix remains in a good state after application, thereby maintaining good coating performance.
  • the thickness of the closed backing film is 20-100 ⁇ m, preferably 20-80 ⁇ m.
  • the closed backing film is selected from a polyester-polyethylene composite film with a metal aluminum liner, and has a thickness of 20 to 100 ⁇ m, preferably 20 to 80 ⁇ m.
  • the backing film is selected from ScotchPak TM 1109, ScotchPak TM 9738 or ScotchPak TM 9730 of 3M Company, preferably ScotchPak TM 9738.
  • the content of colchicine contained in the polymer matrix layer ranges from 10 ⁇ g/cm 2 to 150 ⁇ g/cm 2 , and may also be some other ranges, specifically: 15 ⁇ g/cm 2 to 120 ⁇ g/cm 2 , 20 ⁇ g/cm 2 to 100 ⁇ g/cm 2 , 20 ⁇ g/cm 2 to 25 ⁇ g/cm 2 , 30 ⁇ g/cm 2 to 35 ⁇ g/cm 2 , more specifically, the range may be 20 ⁇ g/cm 2 , 25 ⁇ g/cm 2 , 30 ⁇ g/cm 2 , 35 ⁇ g/cm 2 , 40 ⁇ g/cm 2 , 45 ⁇ g/cm 2 , 50 ⁇ g/cm 2 , 55 ⁇ g/cm 2 , 60 ⁇ g/cm 2 , 65 ⁇ g/cm 2 , 70 ⁇ g/cm 2 , 75 ⁇ g/cm 2 ,
  • the administration area of the patch containing colchicine is 5 cm 2 to 100 cm 2 , or some other ranges, specifically: 10 cm 2 to 90 cm 2 , more specifically the range can be 10 cm 2 , 15 cm 2 , 20 cm 2 , 30 cm 2 , 40 cm 2 , 50 cm 2 , 60 cm 2 , 70 cm 2 , 80 cm 2 .
  • a method for preparing a patch containing colchicine as described in the present invention comprises the following steps:
  • step (2) stirring the mixed solution obtained in step (1) and adding it dropwise to the prescribed amount of the pressure-sensitive adhesive at room temperature at a suitable speed to obtain an adhesive solution;
  • step (3) stirring the glue obtained in step (2) evenly and coating it on the protective layer (release film), and drying the coated polymer matrix layer at a certain temperature to remove the organic solvent;
  • step (3) Compounding the product obtained in step (3) with the backing layer, and punching into required specifications as required to obtain a patch containing colchicine.
  • a method for preparing a patch containing colchicine as described in the present invention comprises the following steps:
  • step (1') stirring the glue obtained in step (1') evenly and coating it on the protective layer (release film), and drying the coated polymer matrix layer at a certain temperature to remove the organic solvent;
  • step (2') Compounding the product obtained in step (2') with a backing layer, and punching into required specifications as required to obtain a patch containing colchicine.
  • the organic solvent in step (1) and/or (1') is selected from one or more of methanol, ethanol or isopropanol, preferably ethanol.
  • the specific operation of removing the organic solvent in step (3) and/or (2') is: drying the coated polymer matrix layer at 35-50°C to remove the organic solvent.
  • An exemplary preparation method is as follows:
  • Step 1) firstly weigh the prescribed amount of colchicine and the penetration enhancer, dissolve them in an appropriate amount of ethanol, and dissolve them under stirring. Depending on the amount added, the stirring time is 15 to 60 minutes to obtain a mixed solution;
  • Step 2) While stirring, add the mixture obtained in step 1) dropwise to the prescription
  • the pressure-sensitive adhesive is added and stirred for 10 to 60 minutes to obtain a glue solution
  • Step 3) the glue obtained in step 2) is stirred evenly and then coated on the release film.
  • the coating thickness is determined according to the final clinical use requirements.
  • the glue is dried in an oven with exhaust function at 35 to 50° C. for 5 to 15 minutes to remove the organic solvent.
  • the specific drying temperature and time are determined according to the coating speed and the amount of residual solvent.
  • Step 4) Compound the product obtained in step 3) with the selected backing film, and punch out into required specifications according to use requirements to obtain a patch containing colchicine.
  • use of the patch of the present invention in preparing a medicament for preventing and/or treating gout and/or pericarditis is disclosed.
  • transdermal administration or “percutaneous administration” used in the present invention refers to a mode of administration in which the active ingredient is delivered into a local or systemic system through the skin or mucous membrane.
  • the terms have the same meaning and can be used interchangeably.
  • polymer matrix layer or "colloid matrix layer” used in the present invention refers to a material combination of a polymer pressure-sensitive adhesive, colchicine, and any other pharmaceutically acceptable excipients included in a transdermal drug delivery system. Generally, the polymer matrix layer is located between the release film and the backing film. The polymer matrix layer is used as the drug delivery layer of the transdermal drug delivery system to form a transdermal drug delivery system of a mixed adhesive and drug type.
  • the polymer matrix layer or the colloidal matrix layer of the present invention has the same meaning and can be used interchangeably.
  • transdermal patch or “transdermal drug delivery system” used in the present invention refers to a system for transdermal drug delivery containing an active ingredient, generally comprising a backing layer and a release film, and a polymer matrix drug delivery layer located between the two layers. Combination mode, generally can be divided into reservoir type and glue-drug mixed type. Transdermal drug delivery system can also be referred to as patch or transdermal patch, these names can be used universally in the present invention.
  • the polymer matrix drug delivery layer generally contains active ingredients, penetration enhancers and/or other pharmaceutical excipients suitable for transdermal drug delivery patches, including but not limited to pressure-sensitive adhesives, fillers, cross-linking agents, antioxidants, ultraviolet absorbers, antibacterial agents, etc.
  • permeability used in the present invention refers to the drug's ability to pass through the skin or mucous membrane by passive diffusion, with the driving force being the concentration difference of the active ingredient on both sides of the skin.
  • the cumulative amount of permeation per unit time and per unit area can be used as an assessment indicator of the permeability of the patch, generally recorded as flux, with a unit of ⁇ g/ cm2 /hr.
  • pressure-sensitive adhesive used in the present invention refers to a class of viscoelastic polymer materials, which can adhere to the surface of most other materials by pressing with very light force and maintain long-term adhesion.
  • Pressure-sensitive adhesives generally include two types, one of which is pressure-sensitive adhesive itself, and the other can achieve the function of pressure-sensitive adhesive by adding tackifiers or plasticizers.
  • Pressure-sensitive adhesives have satisfactory physical properties at room temperature, such as good skin adhesion, maintaining adhesion for a certain period of time, being able to be peeled off without damaging the skin, and being able to control the degree of cold flow, thereby meeting the application requirements.
  • it includes acrylic pressure-sensitive adhesives, silicone pressure-sensitive adhesives and rubber pressure-sensitive adhesives, as well as the above-mentioned pressure-sensitive adhesives through physical mixing or chemical combination to form new mixed pressure-sensitive adhesives, so as to regulate the properties of the pressure-sensitive adhesive to meet special requirements.
  • the term "backing layer” used in the present invention refers to the layer in the transdermal drug delivery patch that the drug cannot penetrate.
  • One surface of the backing layer is directly connected to the polymer matrix layer.
  • the backing layer plays a role in protecting the polymer matrix layer from contact with the surrounding environment and preventing drug loss.
  • the raw material corresponding to the backing layer is generally called a backing film.
  • the material of the backing layer generally includes polyester, polyethylene polyvinyl acetate composite film, polyvinyl chloride, polyurethane, metal foil composite film, non-woven fabric and stretch fabric, etc., and the thickness is generally 10 to 200 ⁇ m.
  • ScotchPak TM 9730, 9701, 9720, 9723 of 3M Company in the United States, China Xiaoshan stretch fabric 6015A, Japan Baoling non-woven fabric EW2080, EW2083, or Shanghai Yingke PE3601 can be used.
  • Backing films of different properties have different physical and chemical properties, such as ductility, air permeability, oxygen permeability, light-shielding, etc., and can be divided into closed backing films and non-closed backing films.
  • the backing layer or backing film of the present invention has the same meaning and can be used interchangeably.
  • light-proof closed backing film used in the present invention refers to a type of backing film with extremely low water, oxygen and light transmission, generally containing metal foils of different thicknesses, such as aluminum foil.
  • release film used in the present invention can also be referred to as a protective layer, which is directly connected to the other surface of the polymer matrix layer. The release film is removed before use of the transdermal patch.
  • an effective dose or “amount to achieve therapeutic effect” or “effectiveness” used in the present invention means that when the transdermal patch is in use, the active ingredient can be delivered through the skin to achieve the required amount for local or systemic effect, thereby achieving a specific pharmacological effect, such as curing, alleviating or controlling a disease or symptom. These terms can be used interchangeably in the present invention.
  • colchicine used in the present invention refers to a phenolic alkaloid existing in the lily family plant Colchicum, which can inhibit cell mitosis and thus play a corresponding pharmacological effect.
  • penetration enhancer used in the present invention refers to a substance that can change the diffusion rate of active ingredients into the skin, and is usually miscible with the active ingredients and uniformly dispersed in the polymer matrix layer.
  • application performance refers to all processes including the peeling force of peeling the patch from the release film, the peeling force of peeling the patch from the application site after application, initial adhesion, sustained adhesion and cold flow.
  • “Peel” refers to the force used to remove the patch from the release film or the skin after application by the backing layer containing the polymer matrix layer.
  • the peeling force should not be too large to cause peeling failure or colloid residue on the skin;
  • “Initial adhesion” refers to the degree of wetting of the backing layer containing the polymer matrix layer and the application site, which reduces the risk of falling off during application;
  • “Shear” refers to the degree of displacement of the patch at the application site, which reflects the application strength during the application process;
  • Cold flow refers to the viscoelastic creep of the polymer matrix layer, which causes the patch to produce black circles during wearing, and may stick to the protective layer and packaging container during storage, affecting the safety and effectiveness of patients.
  • patches need to balance the properties of peeling force, initial adhesion, sustained adhesion and cold flow.
  • the term "colloid properties" used in the present invention refers to the properties of the pressure-sensitive adhesive solution formed after all raw materials and auxiliary materials are added to the pressure-sensitive adhesive during the formulation development process, such as changes in rheology, suitability for coating performance, etc.
  • the term "about” used in the present invention means a range of ⁇ 20% of the value thereafter. In some embodiments, the term “about” means a range of ⁇ 10% of the value thereafter. In the present invention, the term “about” means a range of ⁇ 5% of the numerical value thereafter.
  • serial numbers 1 to 11 are all Henkel polyacrylic acid pressure-sensitive adhesives.
  • Liveo TM BIO-PSA 7-4302 is a polysilicone pressure-sensitive adhesive
  • Liveo TM 7-6302 SilAc Hybrid PSA is a polyacrylic acid and polysilicone composite pressure-sensitive adhesive, commercially available from DuPont.
  • the letter parts of each pressure-sensitive adhesive are omitted in the embodiments and test examples of the present invention, and are replaced by abbreviated numbers.
  • the colchicine-containing patch of the present invention comprises a backing layer, a protective layer and a polymer matrix layer, wherein the polymer matrix layer comprises: colchicine, a permeation enhancer, and a pressure-sensitive adhesive, and the polymer matrix layer is located between the backing layer and the protective layer.
  • the backing layer is selected from a light-proof closed backing film
  • the protective layer is selected from a release film
  • the permeation enhancer not only dissolves the active ingredient but also has a permeation-enhancing effect.
  • Example 1 Solubility of colchicine active ingredient in different types of pressure-sensitive adhesives
  • colchicine and different types of polyacrylic acid pressure-sensitive adhesives can be mutually soluble and dispersed in the colloid to form a uniform solution.
  • Colchicine has a smaller solubility/dispersion ability in the polysilicone pressure-sensitive adhesive 4302, while for the polyacrylic acid and polysilicone composite pressure-sensitive adhesive 6302, colchicine has a similar solubility as in the single polyacrylic acid pressure-sensitive adhesive.
  • the test results show that colchicine can meet certain solubility and dispersion capabilities in different polyacrylic acid pressure-sensitive adhesives, silicone pressure-sensitive adhesives, or acrylic and silicone mixed pressure-sensitive adhesives.
  • FIG1a is an observation image at day 0, from which it can be seen that when the content of colchicine in the 4098 pressure-sensitive adhesive is 5% or less, it is transparent, and when the content is higher, it is translucent;
  • FIG1b is an observation image after 4 months, from which it can be seen that when the content of colchicine in the 4098 pressure-sensitive adhesive is above 5%, crystals are found to precipitate after being placed at room temperature for 4 months, and when the content of colchicine is 5%, crystals are found to precipitate after being placed at room temperature for 4 months.
  • concentration is 0.5 or lower, no crystallization is found, and the adhesive remains transparent and has good viscosity.
  • the stability results show that the maximum solubility of colchicine in general acrylic pressure-sensitive adhesives can reach about 5% without adding a penetration enhancer.
  • Table 4 The weight percentage of colchicine, pressure-sensitive adhesive and penetration enhancer in the polymer matrix layer of Examples 2 to 30
  • the possible reason is that the moisture generated by the breathing of the skin at the application site passes through the colloidal matrix layer and then passes through the backing layer.
  • the solubility of the active ingredient in the colloidal matrix increases, thereby causing its thermodynamic diffusion capacity to decrease, and then showing a significant decrease in permeability.
  • the 3M Scotchpak TM 9738 containing aluminum closed backing film has better permeability.
  • the possible reason is that due to the formation of a closed system, water cannot completely pass through the colloidal matrix layer, thus having little impact on the active ingredients, which is reflected in no obvious change in permeability.
  • the preparation method of the patch containing colchicine is as follows:
  • Step 1) First, weigh the prescribed amount of colchicine and penetration enhancer, add equal weight of anhydrous ethanol and stir to dissolve. The stirring time is determined according to the sample amount, generally 15 to 30 minutes, to obtain a mixed solution:
  • Step 2) weigh a prescribed amount of a polymer pressure-sensitive adhesive, and slowly drop the ethanol mixture of colchicine and a penetration enhancer obtained in step 1) into the pressure-sensitive adhesive while stirring.
  • the dropping time is determined according to the amount of the ethanol solution of colchicine, generally within 5 to 30 minutes. After the dropping is completed, continue stirring for 10 to 30 minutes to evenly disperse the glue matrix to obtain a glue solution;
  • Step 3) Stir the glue obtained in step 2) evenly and then apply it on the 3M Scotchpak TM 9744 release film.
  • the coating thickness is determined according to the final clinical use requirements.
  • the coated polymer matrix is passed through an oven with exhaust function and dried at 35-50°C for 5-15 minutes to remove organic solvents. The specific drying temperature and time are determined by the coating speed and the residual amount of solvent;
  • Step 4) Compound the product obtained in step 3) with 3M Scotchpak TM 9738 backing film, and finally punch and cut into required specifications according to use requirements, and package to obtain a patch containing colchicine.
  • colchicine has the highest solubility in water, followed by a certain solubility in alcohol, alcohol ether or alcohol amine solvents, and a very low solubility in ethyl acetate.
  • Example 24 The patch of Example 24 was tested in a long-term stability environment. The test was carried out in an environment of 30°C and 60% ⁇ 5%RH humidity. The results are shown in Table 8.
  • the in vitro permeation test of the patch of Example 24 was determined by a Franz vertical diffusion cell.
  • the back skin of 30-day-old Bama Xiang pigs was 0.3 mm thick.
  • the receiving solution was a PBS solution with a pH of 7.4, the volume of the receiving cell was 7 mL, the temperature was set at 32 ⁇ 0.1 ° C, and the stirring speed was 200 rpm.
  • Samples were taken at 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h, 3 mL each time, and then an isothermal blank receiving solution was added. Each group of samples was paralleled 3 times. The cumulative permeation amount at each time point was calculated based on the results as shown in Figure 2.
  • water has a significant effect on the permeation behavior of the patch containing colchicine. Due to the high water solubility of colchicine, the water in the receiving medium penetrates into the colloid matrix of the patch, resulting in a significant decrease in permeability (see Test Example 4, permeation data of Bama Xiang pigs on the back).
  • the in vivo permeation test of the patch of Example 24 was conducted to examine the effect of moisture on permeation.
  • Test plan The samples were placed in a high humidity environment of 92.5% RH for 72 hours, one of which had a release film, and the other had the release film peeled off in advance to expose the colloidal matrix directly to the high humidity environment.
  • the in vivo back permeation test was conducted on 30-day-old Bama Xiang pigs, and the results are shown in Figure 3.
  • moisture has a significant effect on the permeation behavior of the patch containing colchicine. Due to the high water solubility of colchicine, the moisture in the environment has a significant effect on the permeation behavior.
  • the moisture absorbed by the patch from the environment will inhibit the permeation of colchicine; after the samples were treated in a high-humidity environment, the in vivo permeation of the samples with release film on the back of Bama miniature pigs decreased slightly, and the in vivo permeation of the samples without the release film on the back of Bama miniature pigs decreased greatly.
  • Test Example 5 Local concentration test in rat joint capsule
  • test prescription 1 72 male SD rats were randomly divided into 6 groups according to their body weight as experimental groups and model control groups.
  • the experimental group was divided into low-, medium- and high-dose groups of test prescription 1, test prescription group 2 and colchicine gavage control group.
  • Six unmodeled rats were taken as normal control group.
  • the specific groups are shown in Table 9. Among them, the low-, medium- and high-dose groups of test prescription 1 corresponded to
  • Test prescription group 2 corresponds to Example 18.
  • test prescription 1 and test prescription 2 were administered 4 and 28 hours after modeling, respectively, and the corresponding test samples (about 0.75 cm 2 , 0.5 ⁇ 1.5 cm, while applying the drug, the rat trunk was restrained with gauze and tape, and the rats were kept in a single cage to prevent the rats from biting the dressings themselves or each other. If the dressings fell during the test, they were recorded and supplemented. After the application of drug administration for 12 hours, the drug administration and trunk restraint were removed. The normal control group and the model control group were applied with blank patches at the same time and in the same way.
  • the colchicine gavage control group was administered once at 4, 16, 28, and 40 hours after model establishment, each time at 0.25 mg/kg, with a dosing volume of 5 mL/kg.
  • Subgroup 1 and subgroup 2 were dissected at 19h and 43h after modeling, respectively.
  • the normal control group was dissected 43h after modeling.
  • the concentration of colchicine in the joint capsule tissue was detected after homogenization. The results are shown in Table 10.
  • Example 29 Four Japanese white rabbits were taken as a blank control group, a low-dose group of test prescription 1 (Example 29), a medium-dose group of test prescription 1 (Example 28), and a high-dose group of test prescription 1 (Example 24), and the drug was administered to four skin sites on the back of each white rabbit.
  • One to two days before administration the hair of the administration site was removed with a hair remover, and the hair removal area was about 5*5cm square.
  • the hair removal cream was applied to the hair removal site, and it was evenly applied to the hair removal site.
  • the hair removal time was about 40 to 60s, and then the hair removal site was rinsed with warm water to ensure that the hair removal cream was rinsed clean, and the water was dried with gauze.
  • Group 1 Eight Bama miniature pigs of a single sex (all male) were taken and randomly divided into two groups according to body weight, 4 pigs/group.
  • Group 1 the patch group, was given 4 patches/pig of the colchicine-containing patch of the present invention percutaneously at the joints of the limbs at a single time, the patch was prepared by Example 30, and the patch specification was 5 cm*7 cm/patch;
  • Group 2 the tablet group, was given 2 tablets/pig (1 mg/pig) of colchicine tablets (purchased from Takata Pharmaceutical Co., Ltd., batch number UX10) per oral gavage at a single time.
  • the first digit of the animal number represents the sex (1 for male, 2 for female); the second digit represents the group (1 for the first group, 2 for the second group, and so on); the last two digits represent the animal sequence number.
  • One animal was dissected from each group at 0.5h, 2h, 4h, and 8h after administration, and plasma, liver, kidney, stomach, duodenum, rectum, joint capsule of four limbs (left anterior, right anterior, left posterior, right posterior), skin at joints, and subcutaneous tissue were collected.
  • Tissue samples collected from Bama miniature pigs were weighed, added with acetonitrile at a ratio of 1:3 (w:v, g/mL), and homogenized on a high-throughput tissue grinder to prepare Bama miniature pig tissue homogenate.
  • the LC-MS/MS method was used to quantitatively detect the concentration of colchicine in various tissue samples of Bama miniature pigs.
  • colchicine was mainly distributed in the skin tissue, followed by the subcutaneous tissue and joint capsule, and relatively less in the plasma, liver, kidney and gastrointestinal tract; the concentration of colchicine in each tissue at different time points was arranged in the following order: 0.5h was limb skin tissue> limb subcutaneous tissue> limb joint capsule, and plasma, liver, kidney, stomach, duodenum, and rectum were all below the quantitative lower limit; 2h was limb skin tissue> limb subcutaneous tissue> limb joint capsule>liver>kidney>plasma>duodenum>stomach>rectum; 4h was limb skin tissue> limb subcutaneous tissue> limb joint capsule>duodenum>plasma>liver>kidney>stomach>rectum; 8h was limb skin tissue> limb subcutaneous tissue> limb joint capsule>kidney>liver>
  • colchicine was mainly distributed in the liver, kidney and gastrointestinal tract, and was relatively less distributed in plasma, skin tissue, subcutaneous tissue and joint capsule; at 0.5h, it 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 2h, it was liver>kidney>duodenum>stomach>rectum>skin tissue of limbs>plasma>subcutaneous tissue of limbs>joint capsule of limbs; at 4h, it was liver>duodenum>kidney>stomach>rectum>skin tissue of limbs>subcutaneous tissue of limbs>joint capsule of limbs>plasma; at 8h, it was liver>kidney>duodenum>stomach>rectum>skin tissue of limbs;
  • the C max ratios of the liver, kidney, duodenum, and rectum of the Bama miniature pig patch group were 0.02-0.22, and the AUC 0-8h ratios were 0.05-0.13, all ⁇ 1; while the C max ratios of the skin tissue, subcutaneous tissue, and joint capsule of the limbs were 57.38-12866.49, and the AUC 0-8h ratios were 41.54-11019.52.
  • colchicine was mainly distributed in the skin tissue, followed by the subcutaneous tissue and joint capsule, while the distribution in plasma, liver, kidney and gastrointestinal tract was relatively less; after the Bama miniature pigs were orally administered colchicine tablets (1 mg/pig), colchicine was mainly distributed in the liver, kidney and gastrointestinal tract, and the distribution in plasma, skin tissue of limbs, subcutaneous tissue of limbs, and joint capsule of limbs was relatively less; the C max and AUC 0-8h of the liver, kidney, duodenum, and rectum of the patch group were lower than those of the tablet group, while the C max and AUC 0-8h of the skin tissue of limbs, subcutaneous tissue of limbs, and joint capsule of limbs were much higher than those of the tablet group.
  • the present invention provides a patch containing colchicine and a preparation method and application thereof, wherein the patch comprises a polymer matrix layer, and the polymer matrix layer comprises the following components by weight percentage: 0.1% to 5.0% of colchicine; 0.005% to 15% of a permeation enhancer; and 80% to 99% of a pressure-sensitive adhesive.
  • the patch containing colchicine of the present invention can achieve a therapeutic effect through skin penetration, has no local irritation during and after application, has no gastrointestinal side effects, has high patient compliance, and has good economic value and application prospects.

Abstract

一种含有秋水仙碱的贴剂及其制备方法和应用，其中贴剂包括高分子基质层，高分子基质层中以重量百分比计，包含如下组分：秋水仙碱0.1％～5.0％；促透剂0.005％～15％；压敏胶80％～99％。以上含有秋水仙碱的贴剂能够经皮透过达到治疗效果的量，贴敷期间及贴敷后无局部刺激性，无胃肠副作用，患者依从性高。

Description

含有秋水仙碱的贴剂及其制备方法和应用
交叉引用
本申请要求2022年9月30日提交的发明名称为“含有秋水仙碱贴剂及其制备方法和应用”的第202211213655.8号中国专利申请的优先权，其全部公开内容通过引用整体并入本文。
技术领域
本发明属于透皮给药技术领域，具体涉及一种含有秋水仙碱的贴剂及其制备方法和应用。
背景技术
秋水仙碱，其化学名称为N-(5,6,7,9-四氢-1,2,3,10-四甲氧基-9-氧代苯并[α]环庚三烯并环庚三烯-7-基)-(S)-乙酰胺，分子式为C22H25NO6，分子量为399.4，淡黄色至淡黄绿色无定形或结晶性粉末，无臭，遇光颜色变深，其化学结构如下：
秋水仙碱具有特殊的三环结构，在高温和光照的条件下不稳定，特别是在光照下产生具有基因毒性的杂质C和杂质G。杂质C和G的化学结构如下：
秋水仙碱作为一种天然植物碱，在公元前人类已经开始使用，并在 1820年首次从秋水仙植物中提取出纯品。秋水仙碱目前被FDA、PDMA、EMA以及NPMA等主要药物监管机构批准，如用于痛风的预防和治疗。痛风已成为仅次于糖尿病的第二大代谢类疾病，秋水仙碱目前是痛风急性发作期的一线治疗及预防药物。除了痛风以外，秋水仙碱还应用于其它疾病的治疗，如地中海热、心血管疾病治疗及预防如心包炎、皮肤病如斯维特综合征(Sweet’s syndrome)及牛皮癣等。
但秋水仙碱由于治疗剂量和毒性剂量接近，导致治疗安全窗口小；同时由于具有肝脏首过效应，导致生物利用度低。目前批准的口服秋水仙碱均具有严重的副作用，如腹痛、恶心、呕吐、腹泻、骨髓抑制、心律不齐以及无精症等，因此，尽管秋水仙碱具有较高的临床有效性，但是这些严重的副作用导致80％以上患者无法坚持口服秋水仙碱的治疗。
经皮给药技术(transdermal drug delivery system，TDDS)主要是指药物通过皮肤或粘膜吸收后在治疗局部部位或全身系统发挥药学作用的给药方式。经皮给药方式具有很多优点，如无胃肠刺激、避免肝脏的首过效应、没有侵害性、长效缓释、能够减少频繁服药的次数、避免口服吸收带来的血药浓度的波动性，从而具有更高的安全性以及良好的患者依从性。
但目前为止，虽然文献中报道了一些通过经皮给药的方式递送秋水仙碱的尝试，但尚未能从临床上解决对秋水仙碱更高的安全性、更好的依从性的需求，因此，亟需一种能够安全且有效递送秋水仙碱的经皮给药系统。发明内容
本发明所要解决的技术问题是克服现有技术中的不足，提供一种含有秋水仙碱的贴剂及其制备方法和应用，其中贴剂包括高分子基质层，高分子基质层中以重量百分比计，包含如下组份：秋水仙碱0.1％～5.0％；促透剂0.005％～15％；压敏胶80％～99％。本发明的含有秋水仙碱的贴剂能够经皮透过达到治疗效果的量，贴敷期间及贴敷后无局部刺激性，无胃肠副作用，患者依从性高。
为解决上述技术问题，本发明采取以下技术方案：
一方面，本发明提供一种含有秋水仙碱的贴剂，包括高分子基质层，高分子基质层中以重量百分比计，包含如下组份：
秋水仙碱  0.1％～5.0％，
促透剂    0.005％～15％，
压敏胶    80％～99％。
优选地，高分子基质层中秋水仙碱的重量百分比为0.25％～4.0％，进一步优选为0.50％～3.5％，更优选为0.50％～3.0％，可以更具体地为0.50％，1.0％，1.5％，2.0％，2.5％，3.0％。
优选地，高分子基质层中促透剂的重量百分比为0.01％～12％，可以具体为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％，10.00％。
优选地，高分子基质层中压敏胶的重量百分比为85％～98％，具体可以为85％，90％，95％，98％。
优选地，含有秋水仙碱的贴剂还包括背衬层；
优选地，含有秋水仙碱的贴剂还包括保护层，高分子基质层位于背衬层与保护层之间。
优选地，促透剂选自能够溶解秋水仙碱且沸点大于或等于150℃的试剂；
优选地，促透剂选自醇类、醇胺类及醇醚类中的一种或多种；
优选地，促透剂的沸点大于或等于180℃；
优选地，醇类选自一元醇和/或二元醇；
优选地，一元醇选自月桂醇、油醇及松油醇中的一种或多种；
优选地，二元醇选自己二醇；
优选地，醇胺类选自氨丁三醇，乙醇胺，二乙醇胺，三乙醇胺，N-羟乙基哌啶，N-羟乙基吡咯烷，N-羟乙基哌嗪，N,N-二丁氨基乙醇及N,N-二乙氨基乙醇中的一种或多种；
优选地，醇醚类选自二乙二醇单乙醚，二乙二醇单丁醚，二乙二醇单 己醚，二丙二醇甲醚，二丙二醇丁醚及一缩二丙二醇中的一种或多种。
优选地，背衬层选自闭合背衬膜或非闭合背衬膜；
优选地，背衬层选自闭合背衬膜；
优选地，闭合背衬膜选自避光闭合背衬膜；
优选地，闭合背衬膜选自金属铝衬的聚酯聚乙烯复合膜；
优选地，闭合背衬膜的厚度为20～100μm；
优选地，保护层选自离型膜。
优选地，压敏胶选自丙烯酸类压敏胶或聚硅酮类压敏胶中的一种或多种；更优选地，压敏胶选自丙烯酸类压敏胶或聚硅酮类压敏胶中的一种或两种。
优选地，高分子基质层中含有的秋水仙碱的含量范围为10μg/cm2～150μg/cm2；
优选地，含有秋水仙碱的贴剂的给药面积为5cm2～100cm2。
另一方面，本发明提供一种制备如本发明所述的含有秋水仙碱的贴剂的方法，包括如下步骤：
(1)将处方量的秋水仙碱和促透剂溶解在有机溶剂中，得到混合液；
(2)将步骤(1)得到的混合液滴加到处方量的压敏胶中，得到胶液；
(3)将步骤(2)得到的胶液涂布在保护层上，去除有机溶剂；
(4)将步骤(3)得到的产品与背衬层复合，冲切，得到含有秋水仙碱的贴剂。
又一方面，本发明提供一种制备如本发明所述的含有秋水仙碱的贴剂的方法，包括如下步骤：
(1’)将处方量的秋水仙碱、促透剂和压敏胶加入到有机溶剂中，混合得到胶液；
(2’)将步骤(1’)得到的胶液涂布在保护层上，去除有机溶剂；
(3’)将步骤(2’)得到的产品与背衬层复合，冲切，得到含有秋水仙碱的贴剂。
优选地，步骤(1)和/或(1’)中的有机溶剂选自甲醇、乙醇或异丙醇中的一种或多种；
优选地，步骤(3)和/或(2’)中去除有机溶剂的具体操作为：在35～50℃条件下烘干，去除有机溶剂。
再一方面，本发明提供一种如本发明所述的含有秋水仙碱的贴剂在制备用于预防和/或治疗痛风和/或心包炎的药物中的应用。
本发明还提供一种治疗痛风和/或心包炎的方法，包括给予需要的受试者治疗有效量的如本发明所述的含有秋水仙碱的贴剂。
本发明还提供一种如本发明所述的含有秋水仙碱的贴剂，其用于预防和/或治疗痛风和/或心包炎。
由于以上技术方案的采用，本发明与现有技术相比具有如下优点：
1、本发明的含有秋水仙碱的贴剂中的秋水仙碱含量能够在经皮透过达到治疗效果的量的同时，在贴敷期间及贴敷后不会产生皮肤的局部刺激性，无胃肠副作用，患者依从性高；
2、本发明的促透剂能够促进秋水仙碱连续可控地经皮透过达到治疗效果的量，且与胶体基质具有良好的相容性；
3、本发明的含有秋水仙碱的贴剂包括和高分子基质层直接连接的背衬层，背衬层在使用的时候起到保护高分子基质层和周边环境接触，防止药物损失的作用；
4、本发明的背衬层优选闭合避光背衬膜，闭合背衬膜具有良好的可控的透过性能，以及在贴敷后胶体基质仍然保持较好的状态从而保持较好的贴覆性能，满足贴剂使用期间的佩戴要求，避光背衬膜具有减少或消除防止秋水仙碱见光分解的风险。
附图说明
图1a为不同含量的秋水仙碱溶解在4098压敏胶中零天的状态图；
图1b为不同含量的秋水仙碱在4098压敏胶中室温放置4个月后的状态图；
图2为实施例24的贴剂的体外透过试验结果图；
图3为实施例24的贴剂在体透过试验结果图；
图4显示雄性巴马小型猪以11.9mg/只的剂量单次经皮给予本发明的含有秋水仙碱的贴剂后各组织或血浆浓度；
图5和图6分别为图4的局部放大图；
图7显示雄性巴马小型猪以1mg/只的剂量单次灌胃给予秋水仙碱片后各组织或血浆浓度。
具体实施方式
本发明具体提供一种含有秋水仙碱的贴剂，包括高分子基质层，高分子基质层中以重量百分比计，包含如下组份：
秋水仙碱  0.1％～5.0％，
促透剂    0.005％～15％，
压敏胶    80％～99％。
秋水仙碱具有一定的皮肤刺激性，而这种刺激性除了和胶体基质组成有关，包括但不限于促透剂的种类和含量、压敏胶的种类及组成，还和秋水仙碱的含量直接相关。因此，为了在保证透过治疗量的前提下减少或消除含有秋水仙碱的贴剂在贴敷处的局部皮肤刺激性，在一些具体的实施例中，秋水仙碱的重量占高分子基质层的干燥重量比为0.1％～5.0％，优选为0.25％～4.0％，进一步优选为0.50％～3.5％，更优选为0.50％～3.0％，可以更具体地为0.50％，1.0％，1.5％，2.0％，2.5％，3.0％。上述含量下，能够保证含有秋水仙碱的贴剂在贴敷期间内连续可控地递送达到治疗效果的量的同时，减少或消除产生皮肤的局部刺激性。
为了达到透过治疗效果的量，本发明含有促透剂。并不是任何类型的促透剂均能实现本发明的目的，这是由于秋水仙碱自身特殊的结构导致其具有优异的水溶性，在醇类及其衍生物中一般易溶，而在极性较小的溶剂如乙酸乙酯中难溶，而本发明所用的压敏胶体系均以乙酸乙酯溶剂为主要体系。因此本发明要解决的一个问题是选择合适的促透剂促进秋水仙碱经 皮透过达到治疗效果剂量，同时能够将秋水仙碱均匀溶解或分散在含有乙酸乙酯为主要溶剂体系的胶体基质中。
在一些具体的实施例中，促透剂包括但不限于醇类如甲醇、乙醇、二乙醇、松油醇、油醇、樟脑、龙脑等，醇醚类如二乙二醇单甲醚等，醇胺类如三乙醇胺、N-羟乙基吡咯烷等，其它如二甲基亚砜(DMSO)、N-甲基吡咯烷酮及油酸等。
本发明意外地发现在经皮给药系统中，一些促透剂具有促透作用的同时，会有潜在破坏压敏胶的胶体性能的风险，特别是在加入更高含量的情况下，例如在一些特殊实施例中加入某些促透剂后溶液状态的压敏胶部分转变为凝胶状态或部分成块状，从而改变胶体流变性，进一步导致涂布失败；在一些特殊实施例中，随着促透剂的含量增加，会进一步破坏胶体性能。因此，本发明在同时考虑促透效果以及胶体性能的基础上选择促透剂。本发明发现某些类型的促透剂与胶体基质具有良好的相容性，并且能起到预期的增加扩散速度的效果。
在一些具体的实施例中，促透剂选自能够溶解秋水仙碱且沸点大于等于150℃的试剂。
在一些具体的实施例中，促透剂选自醇类、醇胺类及醇醚类中的一种或多种。
在一些具体的实施例中，促透剂的沸点大于等于180℃。
在一些具体的实施例中，醇类选自一元醇和/或二元醇。
在一些具体的实施例中，一元醇包括但不限于月桂醇、油醇及松油醇等，二元醇包括但不限于己二醇等，醇胺类包括但不限于氨丁三醇，乙醇胺，二乙醇胺，三乙醇胺，N-羟乙基哌啶，N-羟乙基吡咯烷，N-羟乙基哌嗪，N,N-二丁氨基乙醇及N,N-二乙氨基乙醇等，醇醚类包括但不限于二乙二醇单乙醚，二乙二醇单丁醚，二乙二醇单己醚，二丙二醇甲醚，二丙二醇丁醚及一缩二丙二醇等。
在一些具体的实施例中，促透剂可单独使用，也可组合使用。
促透剂不仅对秋水仙碱具有促透作用，而且一元醇、二元醇、醇胺类或醇醚类促透剂还具有增加秋水仙碱在胶体基质中溶解的能力，因此加入促透剂后，秋水仙碱在胶体基质中的溶解度有增大的趋势。溶解度增大的另外一个方面的含义是相同含量下的秋水仙碱，离达到或接近其最大饱和溶解度的程度更远。然而，秋水仙碱的热力学被动扩散能力和接近饱和溶解度的程度直接相关，一般在达到或接近最大饱和溶解度时具有最高的热力学被动扩散能力。因此，增溶性促透剂的加入增加了胶体基质对秋水仙碱的溶解度，从而一定程度上减小了其被动热力学扩散能力。
因此，促透能力不仅和促透剂种类相关，而且还和促透剂的含量相关。因此某些特殊实施例中促透剂的加入反而降低了透过能力，起不到促透作用。虽然可通过本领域公知的办法，即进一步增加秋水仙碱含量从而再次达到或接近饱和溶解度来增加透过能力，但是由于秋水仙碱具有和含量相关的皮肤局部刺激性，所以限制了通过进一步增加胶体基质中秋水仙碱的含量范围来达到或接近饱和溶解度来进而增加透过能力。
在一些具体的实施例中，促透剂的重量占高分子基质层的干燥重量比为0.005％～15％，优选为0.01％～12％，可以具体为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％，10.00％。
压敏胶选自一种药学上适合经皮给药系统的压敏胶，在一些具体的实施例中，选自基于丙烯酸的高分子化合物的丙烯酸类压敏胶或基于聚硅酮高分子化合物的聚硅酮类压敏胶中的一种。
在一些具体的实施例中，丙烯酸类压敏胶可以是任何均聚物、共聚物、三聚物以及不同丙烯酸的多聚物。根据所含官能团的不同，可为非官能化丙烯酸类压敏胶和官能化丙烯酸类压敏胶，包括但不限于含有羟基、羧基或者同时含有羟基和羧基、氨基以及环氧基等官能团。在一些实施例中，基于加入秋水仙碱活性成份的量以及需要递送的达到治疗效果的量的不同，丙烯酸类压敏胶种类和用量也不同，可以选择官能化丙烯酸类压敏胶， 非官能化丙烯酸类压敏胶，或者两者的混合物。
在一些具体的实施例中，丙烯酸类压敏胶的重量占高分子基质层的干燥重量比为80％～99％，优选为85％～98％，具体可以为85％，90％，95％，98％。
商业上可得的丙烯酸类压敏胶有汉高公司(Henkel)的Duro-Tak产品，如Duro-Tak 87-900A，Duro-Tak 87-9301(非交联，不含醋酸乙烯酯丙烯酸压敏胶，无官能团)，Duro-Tak 87-4098(非交联醋酸乙烯酯丙烯酸压敏胶，无官能团)，Duro-Tak 87-2287(非交联醋酸乙烯酯丙烯酸压敏胶，带有羟基官能团)，Duro-Tak 87-2852(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2196(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2296(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2194(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2516(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2070(交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2353(非交联丙烯酸压敏胶，带有羧基官能团)，Duro-Tak 87-2154(交联丙烯酸压敏胶，带有羧基官能团)和Duro-Tak 87-2510(非交联丙烯酸压敏胶，带有羟基官能团)。
在一些具体的实施例中，聚硅酮类压敏胶的重量占高分子基质层的干燥重量比为90％～99％，优选为95％～99％，具体可以为95％，96％，97％，98％，99％。
商业上可得的聚硅酮类压敏胶有杜邦(DuPont)公司的产品，如LiveoTM 7-6102 SilAc Hybrid PSA，LiveoTM 7-6302 SilAc Hybrid PSA，LiveoTM BIO-PSA 7-4502，LiveoTM BIO-PSA 7-4602，LiveoTM BIO-PSA7-4302和LiveoTM BIO-PSA 7-4102。
秋水仙碱的理化性质导致其在丙烯酸类压敏胶中具有较高的溶解度，而在聚硅酮类压敏胶中的溶解度较小。在一些具体的实施例中，压敏胶可以选自丙烯酸类压敏胶和聚硅酮类压敏胶的混合物。当丙烯酸类压敏胶和聚硅酮类压敏胶混合使用时，根据对秋水仙碱的透过能力以及安全性方面 的综合考虑，可通过调整两者的混合比例来实现。丙烯酸类压敏胶和聚硅酮类压敏胶的混合方式可通过物理混合，即将两种不同性质的压敏胶混合后，搅拌成均匀分散的混悬液；也可通过化学合成的方法得到丙烯酸和硅酮类混合压敏胶。
在一些具体的实施例中，丙烯酸类压敏胶和聚硅酮类压敏胶混合构成的压敏胶占高分子基质层的干燥重量比为90％～99％，优选为95％～99％，具体可以为95％，96％，97％，98％，99％，丙烯酸类压敏胶与聚硅酮类压敏胶的干胶重量比可以为30～70:70～30，具体可以为50:50，40:60，60:40，30:70或70:30。
在一些具体的实施例中，含有秋水仙碱的贴剂还包括背衬层和保护层，高分子基质层位于背衬层与保护层之间。
背衬层与高分子基质层的一个表面直接连接，在使用的时候背衬层起到保护高分子基质层和周边环境的接触，防止药物损失的作用。
保护层选自离型膜，与高分子基质层的另一个表面直接连接。贴剂在使用前去掉离型膜。
在一些具体的实施例中，背衬层选自药学上可接受的背衬膜，包括但不限于聚酯、聚酯和醋酸乙烯复合膜、聚乙烯和醋酸乙酯复合膜、聚氨酯、金属箔如金属铝衬的聚酯聚乙烯复合膜、无纺布、弹力布等。
由于秋水仙碱具有良好的水溶性，因此在贴敷期间由于贴敷处皮肤呼吸的水份进入到胶体基质后，从而对这类水溶性组分在胶体基质中的溶解性产生影响，进而影响到其热力学扩散能力，即透过能力以及贴覆性能，影响的程度取决于贴敷时间以及背衬膜的性质。
因此本发明为了解决贴敷期间由于皮肤呼吸产生的水分对贴剂的透过行为以及贴敷性能的影响，在一些具体的实施例中，背衬层选自闭合背衬膜或非闭合背衬膜。
闭合背衬膜和非闭合背衬膜根据对水份和氧气的透过能力进行划分。非闭合背衬膜对氧气以及皮肤呼吸的水份具有一定的透过性，如无纺布和 弹力布具有相对最高的水份和氧气的透过；闭合背衬膜对氧气以及皮肤呼吸的水份具有阻断作用，如含有金属铝衬的聚酯聚乙烯复合膜具有极低的水份和氧气透过性。根据背衬膜材料的性质及厚度不同，可调节水份以及氧气的透过速度。
在一些具体的实施例中，背衬层选自非闭合背衬膜，非闭合背衬膜便于水份的排出，减少秋水仙碱热力学透过能力的下降从而保持透过能力，但非闭合背衬膜在贴敷一定时间后胶体基质会部分残留于皮肤，导致剥离失败。
在一些具体的实施例中，背衬层选自闭合背衬膜，闭合背衬膜具有良好的可控的透过性能，以及在贴敷后胶体基质仍然保持较好的状态从而保持较好的贴覆性能。闭合背衬膜厚度为20～100μm，优选为20～80μm。
在一些具体的实施例中，闭合背衬膜选自金属铝衬的聚酯聚乙烯复合膜，厚度为20～100μm，优选为20～80μm。
在一些具体的实施例中，背衬膜选自3M公司的ScotchPakTM1109，ScotchPakTM9738或ScotchPakTM9730，优选为ScotchPakTM9738。
在一些具体的实施例中，高分子基质层中含有的秋水仙碱的含量范围为10μg/cm2～150μg/cm2，还可以是一些其他的范围，具体为：15μg/cm2～120μg/cm2，20μg/cm2～100μg/cm2，20μg/cm2～25μg/cm2，30μg/cm2～35μg/cm2，更具体地范围可以是20μg/cm2，25μg/cm2，30μg/cm2，35μg/cm2，40μg/cm2，45μg/cm2，50μg/cm2，55μg/cm2，60μg/cm2，65μg/cm2，70μg/cm2，75μg/cm2，80μg/cm2，85μg/cm2，90μg/cm2，100μg/cm2。
在一些具体的实施例中，根据贴敷时间范围内需要达到的血药浓度或临床效果，含有秋水仙碱的贴剂的给药面积为5cm2～100cm2，还可以是一些其他的范围，具体为：10cm2～90cm2，更具体地范围可以是10cm2，15cm2，20cm2，30cm2，40cm2，50cm2，60cm2，70cm2，80cm2。
在一些具体的实施例中，一种制备如本发明所述的含有秋水仙碱的贴剂的方法，包括如下步骤：
(1)将处方量的秋水仙碱和促透剂溶解在有机溶剂中，得到混合液，其中秋水仙碱与有机溶剂的重量比为1:1；
(2)将步骤(1)得到的混合液搅拌均匀后在室温以合适的速度滴加到处方量的压敏胶中，得到胶液；
(3)将步骤(2)得到的胶液搅拌均匀后涂布在保护层(离型膜)上，在一定温度下将涂好的高分子基质层干燥，去除有机溶剂；
(4)将步骤(3)得到的产品与背衬层复合，按照要求冲切成需要的规格，得到含有秋水仙碱的贴剂。
在一些具体的实施例中，一种制备如本发明所述的含有秋水仙碱的贴剂的方法，包括如下步骤：
(1’)将处方量的秋水仙碱、促透剂和压敏胶加入到有机溶剂中，混合得到胶液；
(2’)将步骤(1’)得到的胶液搅拌均匀后涂布在保护层(离型膜)上，在一定温度下将涂好的高分子基质层干燥，去除有机溶剂；
(3’)将步骤(2’)得到的产品与背衬层复合，按照要求冲切成需要的规格，得到含有秋水仙碱的贴剂。
在一些具体的实施例中，步骤(1)和/或(1’)中的有机溶剂选自甲醇、乙醇或异丙醇中的一种或多种，优选为乙醇。
在一些具体的实施例中，步骤(3)和/或(2’)中去除有机溶剂的具体操作为：在35～50℃条件下将涂好的高分子基质层干燥，去除有机溶剂。
需要说明的是上述制备贴剂所涉及的顺序，每个组分的加入量，搅拌的时间和速度等参数根据所要求的最终使用目的不同而不同。所述参数可根据需要调整。
示例性的制备方法如下：
步骤1)：首先称取处方量的秋水仙碱、促透剂溶解在适量的乙醇中，搅拌下溶解，根据加入量的不同，搅拌时间在15～60分钟，得到混合液；
步骤2)：在保持搅拌的情况下，将步骤1)得到的混合液滴加到处方 量的压敏胶中，继续搅拌10～60分钟，得到胶液；
步骤3)：将步骤2)得到的胶液搅拌均匀后涂布在离型膜上，涂布厚度根据最终临床使用需要确定，通过具有排风功能的烘箱，在35～50℃下烘干5～15分钟，去除有机溶剂，具体烘干温度和时间根据涂布速度、溶剂残留量来决定；
步骤4)：将步骤3)得到的产品与选定的背衬膜复合，按照使用要求冲切成需要的规格，得到含有秋水仙碱的贴剂。
基于贴剂的一般制备方法，文献中其它报道方法也可用于本发明贴剂的制备。
在一些具体的实施例中，公开了本发明贴剂在制备用于预防和/或治疗痛风和/或心包炎的药物中的应用。
术语解释：
除非另有定义，否则本发明使用的所有技术术语和科技术语都具有如在本发明所属领域中通常使用的相同含义。出于解释本说明书的目的，将应用以下定义，并且在适当时，以单数形式使用的术语也将包括复数形式，反之亦然。
本发明所用的术语“透皮给药”或“经皮给药”是指把活性成份通过皮肤或粘膜递送进入局部或全身系统的给药方式。在本发明专利中具有相同意义，可互为通用。
本发明所用的术语“高分子基质层”或“胶体基质层”是指在经皮给药系统中包括的高分子压敏胶、秋水仙碱以及其它药学上可接受的任意辅料的材料组合。一般高分子基质层位于离型膜和背衬膜中间。高分子基质层作为经皮给药系统的给药层，形成胶药混合型的经皮给药系统，本发明高分子基质层或胶体基质层意义相同，可互为通用。
本发明所用的术语“透皮贴剂”或“经皮给药系统”是指含有活性成份的用于经皮给药的系统，一般包括背衬层和离型膜，以及位于两层中间的高分子基质给药层。根据高分子基质给药层里面活性成份和其它组分的 组合方式，一般可分为储库型和胶药混合型。经皮给药系统也可简称为贴剂或透皮贴剂，本发明中这些名称可以通用。高分子基质给药层一般含有活性成份、促透剂和/或其他适用于透皮给药贴剂的药用赋形剂，包括不限于压敏胶、填充剂、交联剂、抗氧化剂、紫外线吸收剂、抗菌剂等。
本发明所用的术语“透过能力”是指药物以被动扩散的方式透过皮肤或粘膜，驱动力为皮肤两边活性成份的浓度差。在单位时间和单位面积的累计透过量，可作为贴剂透过能力的考核指标，一般记为flux，单位为μg/cm2/hr。
本发明所用的术语“压敏胶”是指一类粘弹性高分子材料，当和绝大多数其它材料表面接触时，只需用很轻的力量按压就可以粘附于一起并能保持长久的附着力。压敏胶一般包括两种类型，一种本身即是压敏胶，另外一种可以通过加入增粘剂或增塑剂，从而达到压敏胶的功能。压敏胶在室温下具有令人满意的物理性质，如好的皮肤粘性，在一定时间内保持粘力，能够在不损伤皮肤的情况下剥离并能控制冷流程度，从而满足贴敷要求。一般包括丙烯酸类压敏胶、聚硅酮类压敏胶和橡胶压敏胶，以及上述压敏胶通过物理混合或化学结合的形式，从而形成新的混合压敏胶，以便调控压敏胶的性质满足特殊的要求。
本发明所用的术语“背衬层”是指透皮给药贴剂中药物不能透过的层。背衬层的一个表面与高分子基质层直接连接，在使用的时候背衬层起到保护高分子基质层，使其免于与周边环境接触，防止药物损失的作用。背衬层所对应的原料一般称为背衬膜。背衬层的材料一般包括聚酯、聚乙烯聚醋酸乙烯脂复合膜、聚氯乙烯、聚氨酯、金属箔复合膜、无纺布以及弹力布等，厚度一般为10～200μm。例如，可以使用美国3M公司的ScotchPakTM9730、9701、9720、9723，中国萧山弹力布6015A，日本宝翎无纺布EW2080、EW2083，或上海赢科PE3601。不同性质的背衬膜具有不同的理化性质，如延展性、透气性、透氧性、避光性等，从而可分为闭合背衬膜和非闭合背衬膜。本发明背衬层或背衬膜意义相同，可互为通用。
本发明所用的术语“避光闭合背衬膜”是指水份、氧以及光线等透过极低的一类背衬膜，一般含有不同厚度的金属箔，如铝箔。
本发明所用的术语“离型膜”也可以称为保护层，与高分子基质层的另一表面直接连接。透皮贴剂在使用前去掉离型膜。
本发明所用的术语“透过有效剂量”或者“透过达到治疗效果的量”或者“有效性”是指当透皮贴剂在使用期间，活性成份能够通过皮肤递送足够达到所需要的量，用于局部或系统起效，从而达到特定的药理作用，如治愈、减轻或控制疾病或症状。本发明中这些术语可互为通用。
本发明所用的术语“秋水仙碱”是指存在于百合科植物秋水仙中的一种罩酚酮类生物碱，能抑制细胞有丝分裂，从而起到相应药理作用。
本发明所用的术语“促透剂”是指能够改变活性成份扩散进入皮肤速度的物质，通常能够与活性成份混溶，均匀地分散在高分子基质层中。
本发明所用的术语“贴敷性能”是指包括剥贴剂从离型膜剥离的剥离力、贴敷后贴剂从贴敷处剥离的剥离力、初粘力、持粘力以及冷流等所有过程。其中：“剥离力(peel)”是指含有高分子基质层的背衬层从离型膜或贴敷后从皮肤上去除贴剂时用的力，要求剥离力不可过大导致剥离失败或者胶体残留于皮肤；“初粘力(tack)”是指含有高分子基质层的背衬层和贴敷处的浸润程度，在贴敷期间减小脱落的风险；“持粘力(shear)”是指贴剂在贴敷部位位移程度，反应的是贴敷过程中的贴敷强度；“冷流(cold flow)”是指高分子基质层的粘弹性蠕变，从而导致贴剂在佩戴过程中会产生黑圈，在存储过程中可能会和保护层及包装容器粘黏，影响患者的安全性和有效性。一般贴剂需要平衡剥离力、初粘力、持粘力以及冷流等性质。
本发明所用的术语“胶体性状”指的是处方开发过程中，所有原辅料加入到压敏胶后形成的压敏胶胶液所体现出的性状，如流变学的改变，是否适合涂布性能等。
本发明所用的术语“约”表示其后的数值的±20％的范围。在一些实施方式中，术语“约”表示其后的数值的±10％的范围。在一些实施方式 中，术语“约”表示其后的数值的±5％的范围。
为使本发明的技术方案和有益效果能够更加明显易懂，下面通过结合附图及列举具体实施例的方式进行详细说明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。实施例中未注明具体技术或条件者，通常按照本领域内的文献所描述的常规技术或条件，或者按照产品说明书进行。所用试剂、材料或仪器，如无特殊说明，均为可通过正规商业途径购买得到的常规产品。
在以下实施例和试验例中，压敏胶型号及简写如表1所示。
表1压敏胶型号及简写表
其中序号1～11均为汉高聚丙烯酸类压敏胶。LiveoTM BIO-PSA 7-4302为聚硅酮类压敏胶，LiveoTM 7-6302 SilAc Hybrid PSA为聚丙烯酸和聚硅酮类复合压敏胶，商业来源于杜邦公司。为书写简便，本发明实施例及试验例中省略各压敏胶字母部分，只以简写数字代替。
在以下实施例和试验例中，英文简写如表2所示。
表2英文简写表
本发明含有秋水仙碱的贴剂，包括背衬层、保护层及高分子基质层，高分子基质层包含：秋水仙碱、促透剂、压敏胶，高分子基质层位于背衬层和保护层之间。其中，背衬层选自避光闭合背衬膜，保护层选自离型膜，促透剂起到溶解活性成分的同时还具有促透作用。
实施例1：秋水仙碱活性成分在不同类型的压敏胶中的溶解性
将秋水仙碱以不同的含量溶解在不同性质的压敏胶体系中。结果如表3所示。
表3秋水仙碱活性成分在不同类型的压敏胶中的溶解性表

从表3的结果可以看出，秋水仙碱和不同类型的聚丙烯酸类压敏胶可以互溶，并分散在胶体中形成均匀的溶液。秋水仙碱在聚硅酮类压敏胶4302中具有较小的溶解/分散能力，而对于聚丙烯酸和聚硅酮类复合压敏胶6302，秋水仙碱具有和在单独的聚丙烯酸类压敏胶中类似的溶解能力。试验结果说明，秋水仙碱可在不同聚丙烯酸类压敏胶、硅酮类压敏胶或者丙烯酸类及硅酮类混合压敏胶中均可满足一定的溶解及分散能力。
利用光学放大镜观察了不同含量的秋水仙碱在压敏胶(以4098压敏胶为例)中零天及4个月的稳定性(是否结晶)，结果如附图1所示。
附图1a为零天的观察图像，从中可以看出当秋水仙碱在4098压敏胶中的含量在5％或更低时呈透明状，较高的含量为半透明状；附图1b为4个月后的观察图像，从中可以看出当秋水仙碱在4098压敏胶中的含量在5％以上时，在室温放置4个月后发现有结晶析出，当秋水仙碱的含量在5％ 或更低时，未发现有结晶，仍然保持透明状并且粘性较好。稳定性结果说明秋水仙碱在一般丙烯酸类压敏胶中，在未加促透剂的情况下最高溶解度可达5％左右。
实施例2～30
实施例2～30的高分子基质层中秋水仙碱、压敏胶及促透剂的各重量百分含量如表4所示。
表4实施例2～30高分子基质层中秋水仙碱、压敏胶及促透剂的各重量百分含量表

从表4的结果可以看出，添加不同类型的促透剂，对透过效率变化具有不同的影响。其中，对于非醇类促透剂如薄荷脑、二甲硅油、油酸、IPP、PEG600及DMI等，无论在丙烯酸类压敏胶或硅酮类压敏胶中未表现出明显的促透效果；而对于DGME、HEP、TEOA、DPG等醇类或醇类衍生物，均具有明显的促透效果。但从促透效果看，和醇类的结构有关，如油醇及PEG600，虽然含有醇羟基，但由于随着链长的增加，未表现出促透效果或有稍微的促透。
实施例31～44
实施例31～44含有秋水仙碱的贴剂中各组分及重量百分含量如表5所示。
表5实施例31～44含有秋水仙碱的贴剂中各组分及重量百分含量表

从表5的结果可以看出，不同性质的背衬膜会极大地影响透过性能以及贴敷性能。其中3M ScotchpakTM 9754(聚酯PET)、3MTM CoTranTM 9720&上海赢科3601(聚乙烯PE)、3M ScotchpakTM 9733(聚酯PET及聚醋酸乙烯酯EVA混合膜)、萧山弹力布6015A、日本宝翎无纺布EW2083以及3M CoTranTM 9701(聚氨酯，PU)导致透过能力大大下降，说明非闭合背衬膜会严重影响透过，可能的原因是由于贴敷处皮肤呼吸产生的水分通过胶体基质层，随后经过背衬层，在通过胶体基质层时由于秋水仙碱极好的水溶性，导致活性成分在胶体基质中的溶解能力增大，从而导致其热力学扩散能力下降，进而表现出透过能力下降明显。对于完全非闭合背衬如弹力布或无纺布，进一步导致剥离失败。而含有铝闭合背衬膜3M ScotchpakTM9738具有较好的透过性能，可能的原因是由于形成闭合体系，水分无法完全通过胶体基质层，从而对活性成分的影响较小，表现在透过能力上没有明显改变。
对比例1～12
对比例1～12高分子基质层中秋水仙碱、压敏胶及促透剂的各重量百分含量如表6所示。
表6对比例1～12高分子基质层中秋水仙碱、压敏胶及促透剂的各重量百分含量表
从表6的结果可以看出，添加短支链或直链的醇类的促透剂，会破坏胶体性能，这是因为由于所述短支链或直链的醇类的促透剂具有更高的极性，而硅酮类压敏胶具有极小的极性，虽然由于促透剂的作用可以使秋水仙碱可均匀溶解或分散在压敏胶体系中，但由于促透剂和压敏胶的相容性问题，使部分胶液从均匀的溶液变为具有块状的不溶解的果冻状混合液，进而导致无法完成涂布。
实施例2的制备方法：
该含有秋水仙碱的贴剂的制备方法如下：
步骤1)：首先称取处方量的秋水仙碱和促透剂，加入等重量的无水乙醇中搅拌溶解，搅拌时间根据样品量而定，一般在15～30分钟，得到混合液：
步骤2)：称取处方量的高分子压敏胶，在保持搅拌情况下，将步骤1)得到的秋水仙碱及促透剂的乙醇混合液慢慢滴加到压敏胶中，滴加时间根据秋水仙碱的乙醇溶液量而定，一般在5～30分钟，滴加完毕后，再继续搅拌10～30分钟使胶液基质全部分散均匀，得到胶液；
步骤3)：将步骤2)得到的胶液搅拌均匀后涂布在3M ScotchpakTM9744离型膜上，涂布厚度根据最终临床使用需要确定，将涂布后的高分子基质通过具有排风功能的烘箱，在35～50℃下烘干5～15分钟，去除有机溶 剂，具体烘干温度和时间根据涂布速度、溶剂残留量来决定；
步骤4)：将步骤3)得到的产品与3M ScotchpakTM 9738背衬膜复合，最后按照使用要求冲切成需要的规格，包装，得到含有秋水仙碱的贴剂。
实施例3～44的制备方法与实施例2的制备方法相同。
对比例1～12的制备方法与实施例2的制备方法相同。
试验例1秋水仙碱溶解性试验
称取秋水仙碱原料约2g左右，置于100ml棕色量瓶中，加入10ml溶剂，混匀，置于25℃水浴恒温振荡器中，随时观察，见溶液澄清后继续添加原料。在25℃水浴恒温振荡器中振荡24h后，溶液仍有沉淀，说明该溶液即为饱和溶液。取饱和溶液在离心机中离心后取上清液，稀释到合适浓度，采用外标法测定其浓度，计算溶解度。结果如表7所示。
表7秋水仙碱在不同溶剂中的溶解度表
从表7结果可以看出，秋水仙碱在水中的溶解度最大，其次在醇、醇醚或醇胺类溶剂中具有一定的溶解度，在乙酸乙酯中的溶解度很小。
试验例2长期稳定性试验
将实施例24的贴剂在长期稳定性环境中进行试验。试验在30℃和60％±5％RH湿度的环境中进行。结果如表8所示。
表8实施例24的贴剂在长期稳定性环境中的试验结果表
从表8结果可以看出，含有秋水仙碱的贴剂在稳定性样品放置期间，没有光降解产物C和G的产生，以及其它未知杂质的产生，说明本发明经皮给药系统的稳定。
试验例3体外透过试验
实施例24的贴剂的体外透皮试验通过Franz垂直扩散池测定。30日龄的巴马香猪后背皮，厚度0.3mm。接收液为pH为7.4的PBS溶液，接收池体积为7mL，设定温度32±0.1℃，搅拌速度为200转/分钟。分别于1h，2h，4h，6h，8h，12h取样，每次取样3mL，然后补加等温的空白接受液。每组样品平行3份。根据结果计算各时间点的累积透过量如附图2所示。
从附图2结果可以看出，水分对含有秋水仙碱的贴剂的透过行为影响显著。由于秋水仙碱的高水溶性，接收介质的水分渗入到贴剂的胶体基质后导致透过能力下降明显(参见试验例4，巴马香猪在体背部透过数据)。
试验例4巴马香猪在体透过试验
实施例24的贴剂的在体透过试验，考察水分对透过的影响。试验方案：预先将样品置于92.5％RH的高湿环境72hr，其中一份有离型膜，另外一份预先剥离离型膜以使胶体基质直接暴露在高湿环境中。对30日龄的巴马香猪进行活体后背透皮试验，结果如附图3所示。
从附图3结果可以看出，水分对含有秋水仙碱的贴剂的透过行为影响显著。由于秋水仙碱的高水溶性，环境中的水份对透过行为有显著影响， 贴剂从环境中吸收的水份会抑制秋水仙碱的透过行为；样品经高湿环境处理后，带有离型膜的样品在巴马香猪后背的在体透过稍有下降，去除离型膜的样品在巴马香猪后背的在体透过极大下降。
试验例5大鼠关节囊局部浓度试验
将72只雄性SD大鼠按照体重随机分成6组，作为试验组和模型对照组。其中，试验组分为受试处方1低、中、高剂量组，受试处方2组和秋水仙碱灌胃对照组。试验组和模型对照组每组12只，每组又随机分为两个亚组，分别为亚组1、2，每亚组6只。另取6只未造模大鼠作为正常对照组。具体分组如表9所示。其中，受试处方1低、中、高剂量组分别对应
实施例29、28和24。受试处方2组对应实施例18。
表9大鼠分组表
受试处方1低、中、高剂量组和受试处方2组分别在造模后4、28h进行给药，在踝关节处敷贴相应的受试样品(约0.75cm2，0.5×1.5cm，敷贴给药的同时，用纱布和胶带对大鼠躯干进行束缚，并且单笼饲养，以防大鼠自身或相互之间撕咬敷贴物，试验过程中发现敷贴物掉落，记录并补充敷贴)。敷贴给药持续12h后，去除给药与躯干束缚。正常对照组和模型对照组同时间、同方法敷贴空白贴片。
秋水仙碱灌胃对照组在造模后4、16、28、40h各给药1次，每次0.25mg/kg，给药体积5mL/kg。
分别在造模后19h、43h解剖亚组1、亚组2。正常对照组在造模后43h解剖。关节囊组织匀浆后检测其中秋水仙碱浓度，结果如表10所示。
表10各试验组和对照组中大鼠关节囊组织中的秋水仙碱浓度表
从表10结果可以看出，贴剂贴敷后的大鼠关节囊局部秋水仙碱浓度远高于灌胃。
试验例6兔刺激性试验
取4只日本大耳白兔，分别作为空白对照组、受试处方1低剂量组(实施例29)、受试处方1中剂量组(实施例28)和受试处方1高剂量组(实施例24)，每只大耳白兔背部分4处皮肤进行给药。给药前一至两天用去毛器去除给药部位的被毛，去毛面积约为5*5cm的方形，在去毛部位涂抹脱毛膏，使其均匀涂抹在去毛部位，脱毛时间约为40～60s，随后用温水冲洗脱毛部位，保证脱毛膏冲洗干净，并用纱布将水分吸干。
给药前对脱毛处皮肤进行拍照留存，将事先准备的直径为3cm的供试品贴敷于给药部位，待供试品贴敷8小时后将其取下。去除供试品后60分钟，24、48和72小时肉眼观察皮肤反应，按照表11进行刺激反应及水肿程度评分。
表11皮肤刺激反应评分标准

计算各组每一时间点的皮肤反应积分的平均值，按表12进行刺激强度评价。
表12皮肤刺激强度评价标准
通过对各组给药后的大耳白兔进行刺激性评分，其中空白对照组、受试处方1低剂量组(实施例29)、受试处方1中剂量组(实施例28)和受试处方1高剂量组(实施例24)在给药后各时间点均未观察到红斑和水肿，皮肤刺激强度评价均为0分，可以判定含有秋水仙碱的贴剂在秋水仙碱重量百分含量为0.5％，1％和2％时均没有刺激性。
试验例7秋水仙碱在巴马小型猪体内的局部组织分布研究
取8只巴马小型猪，单一性别(均为雄性)，按体重分层随机分为2组，4只/组，组1贴剂组单次在四肢关节处经皮贴敷给予4贴/只的本发明的含有秋水仙碱的贴剂，贴剂由实施例30制备得到，贴剂规格为5cm*7cm/贴；组2片剂组单次经口灌胃给予2片/只(1mg/只)的秋水仙碱片(购自高田制药株式会社，批号UX10)。
表13各组给药信息
注：动物编号的首位数字代表性别(1为雄性、2分为雌性)；第二位数字代表组别(1为第一组、2为第二组，以此类推)；最后2位数字代表动物顺序号。
每组在给药后0.5h、2h、4h、8h各解剖1只动物，采集其血浆、肝脏、肾脏、胃、十二指肠、直肠、四肢(左前、右前、左后、右后)的关节囊、关节处的皮肤、皮下组织。巴马小型猪采集的组织样本称重后，按1:3(w:v,g/mL)的比例加入乙腈，于高通量组织研磨器上匀浆，制备成巴马小型猪组织匀浆液。
采用LC-MS/MS方法定量检测巴马小型猪各组织样本中秋水仙碱的浓度。
统计巴马小型猪各时间点秋水仙碱在采集各组织中的分布情况，计算各组织和血浆中的药代动力学参数。
结果：
组1贴剂组巴马小型猪四肢关节经皮给予本发明的含有秋水仙碱的贴剂后，如图4-6所示，秋水仙碱主要分布在皮肤组织，其次分布在皮下组织和关节囊，在血浆、肝脏、肾脏及胃肠道的分布相对较少；在不同时间点各组织中秋水仙碱的浓度排列顺序如下：0.5h为四肢皮肤组织>四肢皮下组织>四肢关节囊，血浆、肝脏、肾脏、胃、十二指肠、直肠均低于定量下限；2h为四肢皮肤组织>四肢皮下组织>四肢关节囊>肝脏>肾脏>血浆>十二指肠>胃>直肠；4h为四肢皮肤组织>四肢皮下组织>四肢关节囊>十二指肠>血浆>肝脏>肾脏>胃>直肠；8h为四肢皮肤组织>四肢皮下组织>四肢关节囊>肾脏>肝脏>十二指肠>胃>直肠>血浆；总暴露量(AUC0-8h)的排列顺序为：四肢皮肤组织>四肢皮下组织>四肢关节囊>肝脏>十二指肠>肾脏>血浆>胃>直肠。
组2片剂组巴马小型猪经口灌胃给予秋水仙碱片后，如图7所示，秋水仙碱主要分布在肝脏、肾脏及胃肠道，在血浆、皮肤组织、皮下组织、关节囊的分布相对较少；0.5h为十二指肠>胃>四肢皮肤组织，血浆、肝脏、肾脏、直肠、四肢关节囊、四肢皮下组织均低于定量下限；2h为肝脏>肾脏>十二指肠>胃>直肠>四肢皮肤组织>血浆>四肢皮下组织>四肢关节囊；4h为肝脏>十二指肠>肾脏>胃>直肠>四肢皮肤组织>四肢皮下组织>四肢关节囊>血浆；8h为肝脏>肾脏>十二指肠>胃>直肠>四肢皮肤组织>四肢皮下组织>四肢关节囊>血浆；总暴露量(AUC0-8h)的排列顺序为：十二指肠>肝脏>肾脏>胃>直肠>四肢皮肤组织>四肢皮下组织>四肢关节囊>血浆。
巴马小型猪贴剂组与片剂组相比，肝脏、肾脏、十二指肠、直肠的Cmax比值在0.02～0.22，AUC0-8h比值在0.05～0.13，均<1；而四肢皮肤组织、四肢皮下组织、四肢关节囊的Cmax比值在57.38～12866.49，AUC0-8h比值在41.54～11019.52。
结论：
巴马小型猪经皮给予含有秋水仙碱的贴剂(11.9mg/只)后，秋水仙碱主要分布在皮肤组织，其次分布在皮下组织和关节囊，而在血浆、肝脏、肾脏及胃肠道的分布相对较少；巴马小型猪经口给予秋水仙碱片(1mg/只)后，秋水仙碱主要分布在肝脏、肾脏及胃肠道，在血浆、四肢皮肤组织、四肢皮下组织、四肢关节囊的分布相对较少；贴剂组的肝脏、肾脏、十二指肠、直肠的Cmax和AUC0-8h都小于片剂组，而四肢皮肤组织、四肢皮下组织、四肢关节囊的Cmax和AUC0-8h远大于片剂组。
应当理解，以上实施例均为示例性的，不用于包含权利要求所包含的所有可能的实施方式。在不脱离本公开的范围的情况下，还可以在以上实施例的基础上做出各种变形和改变。同样的，也可以对以上实施例的各个技术特征进行任意组合，以形成可能没有被明确描述的本发明的另外的实施例。因此，上述实施例仅表达了本发明的几种实施方式，不对本发明专利的保护范围进行限制。
工业实用性
本发明提供一种含有秋水仙碱的贴剂及其制备方法和应用，其中贴剂包括高分子基质层，高分子基质层中以重量百分比计，包含如下组份：秋水仙碱0.1％～5.0％；促透剂0.005％～15％；压敏胶80％～99％。本发明含有秋水仙碱的贴剂能够经皮透过达到治疗效果的量，贴敷期间及贴敷后无局部刺激性，无胃肠副作用，患者依从性高，具有较好的经济价值和应用前景。

Claims (10)

  1. 一种含有秋水仙碱的贴剂，其特征在于：所述贴剂包括高分子基质层，所述高分子基质层中以重量百分比计，包含如下组份：
    秋水仙碱  0.1％～5.0％，
    促透剂    0.005％～15％，
    压敏胶    80％～99％；
    优选地，所述高分子基质层中，所述秋水仙碱的重量百分比为0.25％～4.0％，进一步优选为0.50％～3.5％，更优选为0.50％～3.0％；
    优选地，所述高分子基质层中，所述促透剂的重量百分比为0.01％～12％；和/或
    优选地，所述高分子基质层中，所述压敏胶的重量百分比为85％～98％。
  2. 根据权利要求1所述的含有秋水仙碱的贴剂，其特征在于：所述贴剂还包括背衬层；
    优选地，所述贴剂还包括保护层，所述高分子基质层位于所述背衬层与保护层之间。
  3. 根据权利要求1或2所述的含有秋水仙碱的贴剂，其特征在于：所述促透剂选自能够溶解秋水仙碱且沸点大于或等于150℃的试剂；
    优选地，所述促透剂选自醇类、醇胺类及醇醚类中的一种或多种；
    优选地，所述促透剂的沸点大于或等于180℃；
    优选地，所述醇类选自一元醇和/或二元醇；
    优选地，所述一元醇选自月桂醇、油醇及松油醇中的一种或多种；
    优选地，所述二元醇选自己二醇；
    优选地，所述醇胺类选自氨丁三醇，乙醇胺，二乙醇胺，三乙醇胺，N-羟乙基哌啶，N-羟乙基吡咯烷，N-羟乙基哌嗪，N,N-二丁氨基乙醇及N,N-二乙氨基乙醇中的一种或多种；
    优选地，所述醇醚类选自二乙二醇单乙醚，二乙二醇单丁醚，二乙二醇单己醚，二丙二醇甲醚，二丙二醇丁醚及一缩二丙二醇中的一种或多种。
  4. 根据权利要求2所述的含有秋水仙碱的贴剂，其特征在于：所述背 衬层选自闭合背衬膜或非闭合背衬膜；
    优选地，所述背衬层选自闭合背衬膜；
    优选地，所述闭合背衬膜选自避光闭合背衬膜；
    优选地，所述闭合背衬膜选自金属铝衬的聚酯聚乙烯复合膜；
    优选地，所述闭合背衬膜的厚度为20～100μm；
    优选地，所述保护层选自离型膜。
  5. 根据权利要求1或2所述的含有秋水仙碱的贴剂，其特征在于：所述压敏胶选自丙烯酸类压敏胶或聚硅酮类压敏胶中的一种或多种；更优选地，所述压敏胶选自丙烯酸类压敏胶或聚硅酮类压敏胶中的一种或两种。
  6. 根据权利要求1或2所述的含有秋水仙碱的贴剂，其特征在于：所述高分子基质层中含有的秋水仙碱的含量范围为10μg/cm2～150μg/cm2；
    优选地，所述含有秋水仙碱的贴剂的给药面积为5cm2～100cm2。
  7. 一种制备如权利要求1至6中任一项所述的含有秋水仙碱的贴剂的方法，其特征在于：包括如下步骤：
    (1)将处方量的秋水仙碱和促透剂溶解在有机溶剂中，得到混合液；
    (2)将步骤(1)得到的混合液滴加到处方量的压敏胶中，得到胶液；
    (3)将步骤(2)得到的胶液涂布在保护层上，去除有机溶剂；
    (4)将步骤(3)得到的产品与背衬层复合，冲切，得到含有秋水仙碱的贴剂。
  8. 一种制备如权利要求1至6中任一项所述的含有秋水仙碱的贴剂的方法，其特征在于：包括如下步骤：
    (1’)将处方量的秋水仙碱、促透剂和压敏胶加入到有机溶剂中，混合得到胶液；
    (2’)将步骤(1’)得到的胶液涂布在保护层上，去除有机溶剂；
    (3’)将步骤(2’)得到的产品与背衬层复合，冲切，得到含有秋水仙碱的贴剂。
  9. 根据权利要求7或8所述的方法，其特征在于：
    所述步骤(1)和/或(1’)中的有机溶剂选自甲醇、乙醇或异丙醇中的一种或多种；
    优选地，所述步骤(3)和/或(2’)中去除有机溶剂的具体操作为：在35～50℃条件下烘干，去除有机溶剂。
  10. 一种如权利要求1至6中任一项所述的含有秋水仙碱的贴剂在制备用于预防和/或治疗痛风和/或心包炎的药物中的应用。
PCT/CN2023/122148 2022-09-30 2023-09-27 含有秋水仙碱的贴剂及其制备方法和应用 WO2024067722A1 (zh)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
CN1165652A (zh) * 1997-05-22 1997-11-26 李建民 秋水仙碱贴剂
CN101062022A (zh) * 2007-05-31 2007-10-31 天津市中宝制药有限公司 治疗急性痛风的秋水仙碱透皮吸收贴剂及其制备方法
CN108057018A (zh) * 2016-11-08 2018-05-22 北京人福军威医药技术开发有限公司 秋水仙碱外用组合物及其制备方法
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CN101062022A (zh) * 2007-05-31 2007-10-31 天津市中宝制药有限公司 治疗急性痛风的秋水仙碱透皮吸收贴剂及其制备方法
CN108057018A (zh) * 2016-11-08 2018-05-22 北京人福军威医药技术开发有限公司 秋水仙碱外用组合物及其制备方法
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