A hot-melt type patch, a method of preparing the same, and use thereof

Abstract

The application discloses a hot-melt type patch and a preparation method thereof. The adhesive layer comprises a drug and a matrix, the drug is compound 1 or a pharmaceutically acceptable salt thereof, and the prepared hot-melt type patch has good transdermal permeability and stability.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparations, and in particular relates to a hot-melt patch and its preparation method. Background Technology

[0002] 2-(acetoxy)benzoic acid (hereinafter referred to as "Compound 2") is one of the most widely used antipyretic, analgesic, and anti-inflammatory drugs globally, and is often used as a standard for evaluating the efficacy of other drugs. It not only has antipyretic, analgesic, and anti-inflammatory effects, but also exhibits significant antithrombotic effects in vivo, effectively reducing the risk of thrombosis by inhibiting platelet release and aggregation. Therefore, Compound 2 is widely used and has proven effective in the treatment of cardiovascular diseases, especially in the prevention and treatment of coronary heart disease, cerebral infarction, and thrombotic lesions. The structure of Compound 2 is as follows:

[0003] However, the most common adverse reactions to compound 2 are gastrointestinal symptoms, including nausea, vomiting, upper abdominal discomfort or pain. This is because oral administration of compound 2 can directly irritate the gastric mucosa, leading to these symptoms. Long-term use may also cause damage to the gastric mucosa, increasing the risk of gastric ulcers and gastric bleeding.

[0004] To improve the administration route of compound 2 and reduce its side effects, patents CN101484415B and CN104276962B disclose a novel derivative of compound 2 and its composition. These patents specifically mention diethylaminoethyl acetylsalicylate (i.e., diethylaminoethyl 2-(acetoxy)benzoate, referred to herein as "compound 1") and its salts, which can cross biological membranes more efficiently, thus enabling transdermal absorption. This topical administration route not only retains the original therapeutic effects of compound 2 but also, in some cases, provides efficacy comparable to oral compound 2, while reducing direct irritation to the gastrointestinal tract and lowering the incidence of related adverse reactions. The structure of compound 1 is as follows:

[0005] Although the aforementioned patent discloses Compound 1 and its pharmaceutical salt, and indicates that these compounds can be prepared into topical formulations, and lists various available excipients, it does not conduct in-depth research on hot melt patches. Specifically, while the patent mentions possible topical forms, it lacks detailed information on the specific formulation, preparation method, and efficacy evaluation of hot melt patches. Summary of the Invention

[0006] In order to solve the technical problems existing in the prior art, this application provides a hot melt patch, the patch containing an adhesive layer, the adhesive layer comprising a drug and a matrix, wherein the drug is compound 1 or a pharmaceutically acceptable salt thereof.

[0007] Furthermore, a pharmaceutically acceptable salt of compound 1 can be an acid addition salt of compound 1 with monocarboxylic acids such as acetic acid, propionic acid, and butyric acid, or dicarboxylic acids such as oxalic acid, malonic acid, fumaric acid, succinic acid, and maleic acid, or hydroxycarboxylic acids such as glycolic acid, lactic acid, malic acid, citric acid, and tartaric acid, or alkane sulfonic acids such as carbonic acid, methanesulfonic acid, and ethanesulfonic acid, or amino acids such as glutamine, or an acid addition salt of compound 1 with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0008] Furthermore, the matrix can be selected from urethanes, acrylics, styrene, and olefins, preferably styrene matrices, and more preferably styrene block copolymers.

[0009] Furthermore, the adhesive layer also includes at least one of a softener, a tackifier, an antioxidant, a penetration enhancer, a pH adjuster, an anti-irritant, and a solubilizer.

[0010] Furthermore, the softener is selected from one or more of petroleum, silicone oil, liquid rubber, high molecular weight fatty acids, high molecular weight fatty acid esters, polyols, or vegetable oils; The petroleum includes one or more of paraffin oil, aromatic oil, petroleum resin, petrolatum, or liquid paraffin.

[0011] Furthermore, the tackifier is selected from one or more of rosin resin, petroleum resin, terpene resin, polyterpene resin, phenol resin, terpene phenol resin, or xylene resin; The rosin resin includes one or more of rosin ester, hydrogenated rosin, glycerol rosin ester, hydrogenated rosin glycerol ester, rosin acid, or polymerized rosin.

[0012] Furthermore, the penetration enhancer is selected from one or more of clomiphene, azone, menthol, N-methylpyrrolidone, oleic acid, eucalyptus oil, and isopropyl myristate.

[0013] Further, by weight percentage, the adhesive layer comprises: 0.5wt% to 30wt% of drug, 8wt% to 66wt% of matrix, 10wt% to 88wt% of softener and 1wt% to 30wt% of tackifier.

[0014] Further, by weight percentage, the adhesive layer comprises: 5wt%~15wt% of drug, 15wt%~38wt% of matrix, 45wt%~68wt% of softener, 5wt%~18wt% of tackifier and 0.5wt%~5wt% of penetration enhancer.

[0015] On the other hand, the present invention provides a method for preparing the above-mentioned hot melt patch, comprising the following steps: mixing the matrix, the softener, the drug, the tackifier and the penetration enhancer, heating and melting them, and stirring evenly to obtain a paste; uniformly applying the paste to the backing layer, then bonding it with the protective layer, and finally cutting it into a suitable size to obtain the hot melt patch.

[0016] On the other hand, the present invention provides the use of the above-described transdermal patch, or the hot-melt patch obtained by the above-described preparation method, in a medicament for treating fever, analgesia, and inflammation.

[0017] Compared with the prior art, the present invention has the following technical effects: The compound 1 hot-melt patch prepared in this invention exhibits excellent transdermal and permeability properties, along with suitable rheological properties and reasonable adhesion, providing a good user experience, easy peeling, and excellent stability. This hot-melt patch not only has uniform content and controllable related substance content, but also shows stable drug release characteristics in both in vitro and in vivo release tests. Skin irritation tests show that this hot-melt patch has no skin irritation, ensuring safety. Pharmacodynamic and pharmacokinetic studies demonstrate that this hot-melt patch has significant therapeutic effects, and the absorption, distribution, metabolism, and excretion processes of the drug in vivo are stable and reliable. Furthermore, stability studies show that this hot-melt patch maintains its physical, chemical, and biological properties under different storage conditions, ensuring long-term effectiveness. Detailed Implementation

[0018] The technical solutions in the embodiments of this application will be clearly described below with reference to the examples. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0019] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0020] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0021] Compound 1, "2-(acetoxy)benzoate diethylaminoethyl ester," is a prodrug of compound 2. After entering the body, it is converted into the parent drug, compound 2, through enzymatic reactions, chemical changes, or other mechanisms. Patents CN101484415B and CN104276962B both demonstrate that compound 1 or its pharmaceutically acceptable salt can form compound 2 in the body and exert the therapeutic effects of compound 2.

[0022] The "hot melt patch" described in this invention is a type of transdermal patch. It uses hot melt pressure-sensitive adhesive as its base, a heat-soluble polymer that is solid at room temperature. It is applied by heating to a molten state and then quickly adheres to the skin upon cooling. As a modern medical product, the hot melt patch combines hot melt adhesive technology with the treatment concepts of traditional plasters, exhibiting multiple significant advantages. Its adhesiveness is excellent after heating, allowing it to adhere tightly to the skin and ensure effective drug delivery to the affected area. No additional solvents or adhesives are required during use, simplifying the process and improving ease of use and comfort. Furthermore, the hot melt patch possesses a certain degree of water resistance, making it more suitable for daily life. From an environmental perspective, it is typically solvent-free, does not produce harmful or toxic fumes, has high safety, and is environmentally friendly, causing no secondary pollution or harm to human health. Simultaneously, the hot melt patch cures quickly, completing adhesion in a very short time, and its adhesive strength is stable, unaffected by changes in temperature and humidity in the working environment, thus ensuring strong adhesion. This provides patients with a more efficient and convenient new treatment option.

[0023] To maximize the medicinal efficacy of Compound 1 or its pharmaceutically acceptable salts, this invention proposes an innovative hot-melt patch. Its unique feature lies in its carefully optimized drug delivery system, utilizing the properties of hot-melt adhesives to ensure efficient and stable skin penetration of Compound 1. The hot-melt patch rapidly softens and adheres tightly to the skin upon heating, a characteristic that not only improves transdermal drug delivery efficiency but also enhances patient comfort. Simultaneously, the patch is designed with skin compatibility in mind, reducing irritation and allergic reactions, thereby prolonging the duration of drug action while effectively reducing the probability of side effects.

[0024] Specifically, the hot-melt patch contains an adhesive layer comprising a drug and a matrix, wherein the drug is compound 1 or a pharmaceutically acceptable salt thereof.

[0025] In one embodiment of the present invention, a pharmaceutically acceptable salt of compound 1 may be an acid addition salt of compound 1 with monocarboxylic acids such as acetic acid, propionic acid, and butyric acid, or dicarboxylic acids such as oxalic acid, malonic acid, fumaric acid, succinic acid, and maleic acid, or hydroxycarboxylic acids such as glycolic acid, lactic acid, malic acid, citric acid, and tartaric acid, or alkane sulfonic acids such as carbonic acid, methanesulfonic acid, and ethanesulfonic acid, or amino acids such as glutamine, or an acid addition salt of compound 1 with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0026] In one embodiment of the present invention, one or more of the above-mentioned compound 1 and its salts may be used. Furthermore, from the viewpoint of dispersibility in the adhesive layer and transdermal absorption, the free (basic) form of compound 1 is preferred.

[0027] In one embodiment of the present invention, compound 1 in the form of a free base can be prepared by conventional methods in the art or purchased through other commercial channels.

[0028] This invention does not restrict the source of the drug. It can be synthesized or purchased using existing technologies, such as the methods disclosed in patents CN101484415B and / or CN104276962B to prepare compound 1 or its pharmaceutically acceptable salt, or purchased through other commercial channels.

[0029] The content of compound 1 in hot-melt patches is not particularly limited, but considering dispersibility and transdermal absorption in the adhesive layer, it can be 0.5wt%~30wt%, 1wt%~30wt%, 1.5wt%~29wt%, 2wt%~28wt%, 2.5wt%~27wt%, 3wt%~26wt%, 3.5wt%~25wt%, 4wt%~24wt%, 4.5wt%~23wt%, 5wt%~22wt%, 5.5wt%~21wt%, 6 The concentrations are wt%~20wt%, 6.5wt%~19wt%, 7wt%~18wt%, 7.5wt%~17wt%, 8wt%~16wt%, 8.5wt%~15wt%, 9wt%~14wt%, 9.5wt%~13wt%, 10wt%~12wt%, 10.5wt%~11wt%, preferably 0.5wt%~25wt%, more preferably 1wt%~20wt%, more preferably 5wt%~15wt%, and even more preferably 1wt%~10wt%. Furthermore, considering the peel resistance of the patch during bathing, a concentration of 15wt% or less is preferred.

[0030] The term "matrix" used in this invention refers to an elastomer that softens and exhibits fluidity when heated, but reverts to the thermoplastic properties of a rubber elastomer when cooled. Examples of matrices include urethanes, acrylics, styrene, and olefins. In particular, from the viewpoint of achieving both sufficient skin adhesion and low skin irritation, which are the objectives of this invention, styrene-based matrices, especially styrene-based block copolymers, are preferred.

[0031] Styrene-based block copolymers used as the matrix can specifically include: styrene-butadiene block copolymers, styrene-butadiene-styrene block copolymers, styrene-isoprene block copolymers, styrene-isoprene-styrene block copolymers, styrene-ethylene / butene block copolymers, styrene-ethylene / butene-styrene block copolymers, styrene-ethylene / propylene block copolymers, styrene-ethylene / propylene-styrene block copolymers, styrene-isobutylene block copolymers, and styrene-isobutylene-styrene block copolymers. Furthermore, in the above examples, "ethylene / butene" indicates a copolymer block of ethylene and butene, and "ethylene / propylene" indicates a copolymer block of ethylene and propylene. Only one type of styrene-based block copolymer can be used, or two or more types can be used in combination.

[0032] Among the aforementioned styrene block copolymers, in addition to possessing sufficient skin adhesion and low skin irritation, from the viewpoint of availability and operability of patch products, one or more selected from styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers are preferred. From the viewpoint of adhesion, a mixture of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers is particularly preferred. Furthermore, if the mixing ratio of styrene-isoprene block copolymers is too low, skin adhesion tends to decrease; if it is too high, the shape retention of the adhesive layer tends to decrease, and when applied to the skin, undesirable situations such as residue on the skin after peeling may occur. Therefore, the mixing ratio of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers, by weight, is preferably 10 / 90 to 82 / 18, more preferably 20 / 80 to 75 / 25, and even more preferably 30 / 70 to 70 / 30.

[0033] For the purposes of this invention, the styrene-isoprene-styrene block copolymer preferably has a styrene content of 5 wt% to 60 wt%, more preferably 10 wt% to 50 wt%. Furthermore, the weight-average molecular weight, as measured by gel filtration chromatography, is preferably 20,000 to 500,000, more preferably 30,000 to 300,000. Additionally, as the styrene-isoprene block copolymer, the styrene content in the copolymer is preferably 5 wt% to 50 wt%, more preferably 10 wt% to 40 wt%. Furthermore, the weight-average molecular weight, as measured by gel filtration chromatography, is preferably 10,000 to 500,000, more preferably 20,000 to 300,000. Furthermore, the mixture of ethylene-isoprene-styrene block copolymer and styrene-isoprene block copolymer preferably has a weight-average molecular weight, as measured by gel filtration chromatography, of 20,000 to 500,000, more preferably 30,000 to 300,000.

[0034] Styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers can each be copolymers manufactured using methods known to them. Furthermore, commercially available products that satisfy the aforementioned properties can be used for both styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers. Additionally, mixtures of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers are also commercially available; preferably, commercially available mixtures of styrene-isoprene-styrene block copolymers and styrene-isoprene block copolymers mixed in the aforementioned mixing ratios and satisfying the aforementioned properties are used.

[0035] Commercially available products include, for example, "KRATOND1161", "KRATOND1163", "KRATON D1113" and "KRATON D1119" manufactured by KRATON POLYMERS, and "JSR SIS5229", "JSR SIS5403" and "JSR SIS5505" manufactured by JSR.

[0036] If the matrix content in the adhesive layer is too low, the shape retention of the adhesive layer tends to decrease; if it is too high, the skin adhesion tends to be insufficient. Therefore, the matrix content in the adhesive layer of the hot-melt patch of the present invention is preferably 8 wt% or more, more preferably 10 wt% or more, even more preferably 12 wt% or more, even more preferably 15 wt% or more, even more preferably 18 wt% or more, particularly preferably 20 wt% or more, even more preferably 24 wt% or more, and most preferably 28 wt% or more. Furthermore, it is preferably 66 wt% or less, more preferably 65 wt% or less, even more preferably 64 wt% or less, even more preferably 49 wt% or less, and even more preferably 39 wt% or less.

[0037] Furthermore, as a more specific preferred embodiment, the matrix content in the adhesive layer can be 8wt%~66wt%, 9wt%~65wt%, 10wt%~64wt%, 11wt%~63wt%, 12wt%~62wt%, 13wt%~61wt%, 14wt%~60wt%, 15wt%~59wt%, 16wt%~58wt%, 17wt%~57wt%, 18wt%~56wt%, 19wt%~55wt%, 20wt%~54wt%, 21wt%~53wt%, 22wt%~52wt%, 23wt% The preferred values ​​are ~51wt%, 24wt%~50wt%, 25wt%~49wt%, 26wt%~48wt%, 27wt%~47wt%, 28wt%~46wt%, 29wt%~45wt%, 30wt%~44wt%, 31wt%~43wt%, 32wt%~42wt%, 33wt%~41wt%, 34wt%~40wt%, 35wt%~39wt%, 36wt%~38wt%, more preferably 10wt%~64wt%, particularly preferably 12wt%~49wt%, and most preferably 15wt%~38wt%.

[0038] In one embodiment of the present invention, the adhesive layer further comprises at least one of a softener, a tackifier, an antioxidant, a penetration enhancer, a pH adjuster, an anti-irritant, and a cosolvent.

[0039] In one embodiment of the present invention, the softener includes petroleum (paraffin oil, aromatic oil, etc.), silicone oil, liquid rubber (polybutene, liquid isoprene rubber, etc.), high molecular weight fatty acids, high molecular weight fatty acid esters, polyols (polyethylene glycol, propylene glycol, diethylene glycol, cyclopropylene glycol, glycerin, ethylene glycol salicylate, etc.), vegetable oils (olive oil, eucalyptus oil), etc.

[0040] In one embodiment of the invention, the petroleum includes one or more of paraffin oil, aromatic oil, petroleum resin, petrolatum, or liquid paraffin.

[0041] Softeners have the ability to soften the adhesive layer and improve its adhesion to the skin during application, and can control the adhesion to the skin and reduce physical irritation to the skin.

[0042] In one embodiment of the present invention, the softener is preferably a non-volatile hydrocarbon oil, preferably a chain-type saturated hydrocarbon with about 20 to 40 carbon atoms or a chain-type unsaturated hydrocarbon with about 20 to 40 carbon atoms, such as liquid paraffin, squalene, squalane, and squalane. Liquid paraffin is more preferred from the viewpoint of ease of acquisition. Liquid paraffin is a colorless and odorless liquid mixture of alkanes with 20 or more carbon atoms; however, in the present invention, substances conforming to the specifications specified in the Chinese Pharmacopoeia, Japanese Pharmacopoeia, and United States Pharmacopeia are preferred. The non-volatile hydrocarbon oil preferably has high viscosity; from the viewpoint of adhesion, high-viscosity liquid paraffin is particularly preferred.

[0043] Specifically, the non-volatile hydrocarbon oil preferably has a kinematic viscosity of 60 mmHg at 40°C. 2 / s or higher, further preferably 70mm 2 / s or higher, with 80mm being particularly preferred. 2 / s or higher. Furthermore, there is no particular upper limit to the kinematic viscosity, but considering factors such as ease of operation and ease of obtaining, 500 mm is preferred. 2 Below / s, preferably 250mm 2 / s or less.

[0044] The patch of the present invention preferably contains the aforementioned softener in a weight ratio of more than 50 parts by weight and less than 800 parts by weight relative to 100 parts by weight of the matrix. If the content of the softener relative to 100 parts by weight of the matrix is ​​more than 800 parts by weight, it is difficult to maintain the shape of the adhesive layer. On the other hand, if the content of the softener is less than 50 parts by weight, the matrix tends to become too hard and insufficient skin adhesion may not be achieved, especially sometimes the follow-through relative to skin movement during application becomes poor, and the patch may fall off during application. From this point of view, the content of the softener in the adhesive layer is preferably 51 parts by weight to 800 parts by weight relative to 100 parts by weight of the matrix, more preferably 60 parts by weight to 600 parts by weight, and particularly preferably 70 parts by weight to 500 parts by weight.

[0045] Furthermore, even within this range, if the content of the softener is too high, there is a tendency for the peel stress in the adhesive properties to decrease, and there is a tendency for adhesive overflow during storage and application, easily resulting in poor adhesion to packaging materials and clothing. On the other hand, if the content of the softener is too low, there is a particular possibility of reduced skin adhesion and patch detachment during sweating or bathing. From this perspective, the content of non-volatile hydrocarbon oil in the adhesive layer is preferably 80 to 400 parts by weight relative to 100 parts by weight of the matrix, more preferably 90 to 350 parts by weight, and particularly preferably 100 to 300 parts by weight. Furthermore, the kinematic viscosity at 40°C is less than 80 mm. 2When liquid paraffin at a concentration of / s is used as a softener, the softener content in the adhesive layer is preferably 150 to 250 parts by weight relative to 100 parts by weight of the matrix, more preferably 151 to 250 parts by weight, particularly preferably 153 to 248 parts by weight, and most preferably 155 to 245 parts by weight.

[0046] Furthermore, the content of the softener in the adhesive layer is preferably 20 wt% or more, more preferably 25 wt% or more, even more preferably 26.5 wt% or more, even more preferably 35 wt% or more, even more preferably 45 wt% or more, and particularly preferably 50 wt% or more. Additionally, it is preferably 88 wt% or less, more preferably 85 wt% or less, even more preferably 83 wt% or less, even more preferably 70 wt% or less, and even more preferably 68 wt% or less.

[0047] In addition, as a more specific preferred embodiment, the content of the softener in the adhesive layer can be 10wt%~88wt%, 11wt%~87wt%, 12wt%~86wt%, 13wt%~85wt%, 14wt%~84wt%, 15wt%~83wt%, 16wt%~82wt%, 17wt%~81wt%, 18wt%~80wt%, 19wt%~79wt%, 20wt%~78wt%, 21wt%~77wt%, 22wt%~76wt%, 23wt%~75wt%, 24wt%~74wt%, 25wt%~73wt%, 26wt%~72wt%, 27wt%~71wt%, 28wt%~70wt%, 29wt%~69wt%, 30wt%~68wt%, 31wt%~67wt%, 32wt%~66wt%, or 33wt%. The preferred wt% values ​​are ~65wt%, 34wt%~64wt%, 35wt%~63wt%, 36wt%~62wt%, 37wt%~61wt%, 38wt%~60wt%, 39wt%~59wt%, 40wt%~58wt%, 41wt%~57wt%, 42wt%~56wt%, 43wt%~55wt%, 44wt%~54wt%, 45wt%~53wt%, 46wt%~52wt%, 47wt%~51wt%, and 48wt%~50wt%, preferably 20wt%~88wt%; further preferably 25wt%~85wt%; more preferably 26.5wt%~83wt%; even more preferably 35wt%~80wt%; even more preferably 35wt%~70wt%; even more preferably 50wt%~70wt%; and most preferably 45wt%~68wt%.

[0048] In one embodiment of the present invention, the tackifier is selected from one or more of rosin resin, petroleum resin, terpene resin, polyterpene resin, phenol resin, terpene phenol resin or xylene resin.

[0049] In one embodiment of the present invention, the rosin resin includes one or more of rosin ester, hydrogenated rosin, glycerol rosin ester, hydrogenated rosin glycerol ester, rosin acid, or polymerized rosin.

[0050] In hot melt patches, tackifiers play several crucial roles. They significantly enhance the patch's adhesion to the skin, ensuring stable attachment in various environments, and improve skin compatibility, reducing the likelihood of irritation and allergic reactions. Furthermore, tackifiers control drug release rates, provide physical protection to maintain drug stability, and facilitate drug penetration through the stratum corneum, thereby improving bioavailability. In addition, tackifiers improve processing performance, making the production process smoother and facilitating the formation of a uniform and robust patch structure.

[0051] If the content of the tackifier in the adhesive layer is too low or too high, it will not function properly. Therefore, the tackifier content in the adhesive layer of the hot melt adhesive of the present invention is preferably 1 wt% or more, more preferably 5 wt% or more, more preferably 10 wt% or more, and even more preferably 12 wt% or more. In addition, it is preferably 30 wt% or less, more preferably 25 wt% or less, even more preferably 20 wt% or less, and even more preferably 18 wt% or less.

[0052] Furthermore, as a more specific preferred embodiment, the tackifier content in the adhesive layer can be 1wt%~30wt%, 1wt%~29wt%, 2wt%~29wt%, 3wt%~28wt%, 4wt%~27wt%, 5wt%~26wt%, 6wt%~27wt%, 7wt%~26wt%, 8wt%~25wt%, 9wt%~24wt%, 10wt%~23wt%, 11wt%~22wt%, 12wt%~21wt%, 13wt%~20wt%, 14wt%~19wt%, 15wt%~18wt%, 16wt%~17wt%, more preferably 5wt%~30wt%, 10wt%~25wt%, particularly preferably 12wt%~20wt%, and most preferably 12wt%~18wt%.

[0053] In one embodiment of the present invention, the penetration enhancer is selected from one or more of clomiphene, azone, menthol, N-methylpyrrolidone, oleic acid, eucalyptus oil, and isopropyl myristate.

[0054] In transdermal patches, penetration enhancers can increase the ability of drug molecules to penetrate the skin, thereby improving drug bioavailability. This invention does not limit the type of penetration enhancer; each can be added in appropriate amounts.

[0055] If the content of the penetration enhancer in the adhesive layer is too low or too high, it will not be able to exert its function effectively. Therefore, the content of the penetration enhancer in the adhesive layer of the hot melt adhesive of the present invention is preferably 0.5 wt% or more, more preferably 1 wt% or more, and even more preferably 2 wt% or more. In addition, it is preferably 30 wt% or less, more preferably 20 wt% or less, even more preferably 10 wt% or less, and even more preferably 5 wt% or less.

[0056] Furthermore, as a more specific preferred embodiment, the content of the penetration enhancer in the adhesive layer can be 0.5wt%~30wt%, 1wt%~30wt%, 1.5wt%~29wt%, 2wt%~28wt%, 2.5wt%~27wt%, 3wt%~26wt%, 3.5wt%~25wt%, 4wt%~24wt%, 4.5wt%~23wt%, 5wt%~22wt%, 5.5wt%~21wt%, 6wt%~20wt%, 6.5wt%~19wt%, 7wt%~18wt%, 7.5wt%~17wt%, 8wt%~16wt%, 8.5wt%~15wt%, 9wt%~14wt%, 9.5wt%~13wt%, 10wt%~12wt%, 10.5wt%~11wt%, more preferably 0.5wt%~20wt%, particularly preferably 0.5wt%~10wt%, and most preferably 0.5wt%~5wt%.

[0057] Antioxidants are used to prevent the hot melt adhesive from undergoing oxidative decomposition during processing and use, thereby avoiding discoloration, brittleness, and loss of adhesiveness. This invention does not limit the type of antioxidant; commonly used antioxidants include butylated hydroxytoluene (BHT) and its analogues, p-octylphenol, sodium benzoate, dodecyl thiodipropionate, etc., and each antioxidant can be added in appropriate amounts.

[0058] pH adjusters are used to adjust the pH value of hot melt adhesives or pharmaceutical preparations to increase stability and solubility, and reduce irritation. This invention does not limit the type of pH adjuster; commonly used pH adjusters include hydrochloric acid, sodium hydroxide, sodium bicarbonate, and acetate-sodium acetate buffer, etc., and each pH adjuster can be added in appropriate amounts.

[0059] Anti-irritants are used to reduce skin irritation from medications or patches, improving safety and comfort during use. This invention does not limit the type of anti-irritant, which can be added in appropriate amounts.

[0060] Solubilizers are used to increase the solubility of drugs and improve their physical and chemical stability. Commonly used solubilizers include polysorbates (Tween derivatives), poloxamer (Pranic), lecithin, etc., and can be added in appropriate amounts.

[0061] In one embodiment of the present invention, the hot-melt patch, by weight percentage, comprises the following adhesive layer: 0.5wt%~30wt% of drug, 8wt%~66wt% of matrix, 10wt%~88wt% of softener, and 1wt%~30wt% of tackifier. Preferably, the composition is 0.5wt%~25wt% of drug, 10wt%~64wt% of matrix, 26.5wt%~83wt% of softener, and 5wt%~25wt% of tackifier. More preferably, the composition is 1wt%~10wt% of drug, 12wt%~49wt% of matrix, 45wt%~68wt% of softener, and 12wt%~20wt% of tackifier. Even more preferably, the composition is 5wt%~15wt% of drug, 15wt%~38wt% of matrix, 45wt%~68wt% of softener, 12wt%~18wt% of tackifier, and 0.5wt%~5wt% of penetration enhancer.

[0062] The "wt%" mentioned in this invention refers to the mass percentage, which is used to express the mass proportion of a substance in a mixture or solution.

[0063] In one embodiment of the present invention, the hot melt patch further includes a backing layer and a protective layer, wherein a drug-adhesive layer is located between the backing layer and the protective layer.

[0064] In one embodiment of the present invention, the preparation method of the hot melt patch is as follows: the matrix and part of the softener are heated and melted, the drug and the thickener are added, heated and melted and stirred evenly, then the penetration enhancer and the remaining softener are added and stirred evenly to obtain a paste; the paste is evenly coated on the backing layer, then bonded to the protective layer, and finally cut into a suitable size to obtain the hot melt patch.

[0065] In one embodiment of the present invention, the preparation method of the hot melt adhesive includes the following steps: (1) Add some softener to the mixing pot, heat and stir until melted, and control the material temperature.

[0066] (2) Add the matrix and part of the softener to the material obtained in step (1), heat and stir until melted, and control the material temperature.

[0067] (3) Add thickener and some softener to the material obtained in step (2), heat and stir until melted, and control the material temperature.

[0068] (4) Disperse the drug into a portion of the softener to obtain a drug mixture.

[0069] (5) Add the penetration enhancer to part of the softener to obtain a mixture.

[0070] (6) Add the drug mixture obtained in step (4) to the material obtained in step (3), heat and stir until melted, and control the material temperature.

[0071] (7) Add a penetration enhancer and the remaining softener to the material obtained in step (6), heat and stir until melted, and control the material temperature.

[0072] (8) Vacuum and stir the material obtained in step (7) to remove air bubbles.

[0073] (9) Coat the colloid obtained in step (8), cover it with a backing, and add a protective layer to obtain a hot melt adhesive patch.

[0074] There is no limitation on the thickness of the adhesive layer of the patch of the present invention, which is preferably 20~500μm, more preferably 70~300μm.

[0075] The backing material can be selected from polyethylene, aluminum foil, polypropylene, and polyester, etc. The protective film material is selected from polyethylene, polypropylene, etc.

[0076] The hot-melt patch of the present invention can be used to prepare drugs for treating and / or relieving fever, analgesia, and anti-inflammatory related diseases or symptoms. Specifically, the fever-related symptoms include, but are not limited to, the common cold, influenza, acute upper respiratory tract infection, postoperative or post-traumatic inflammation, and fever caused by rheumatic immune diseases; the analgesic related symptoms include, but are not limited to, mild to moderate headache, migraine, toothache, muscle pain, joint pain, neck, shoulder, back and leg pain, soft tissue injury pain, sprain pain, strain pain, overuse pain, neuralgia, sciatica, dysmenorrhea, mild to moderate postoperative pain, and pain during an acute gout attack; the anti-inflammatory related diseases or symptoms include, but are not limited to, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, tendinitis, tenosynovitis, synovitis, fasciitis, frozen shoulder, tennis elbow, acute gouty arthritis, and postoperative or post-traumatic local aseptic inflammation.

[0077] Example 1

[0078] Preparation process: After heating and melting the matrix and softener in a mixing pot, add the thickener, heat and melt it, and stir until uniform. Then add the penetration enhancer and the remaining softener, stir until uniform, and finally add compound 1 and stir until uniform to obtain a paste. Apply the paste evenly to the backing layer, then attach it to the protective layer, and finally cut it into the appropriate size.

[0079] (1) Weigh out the prescribed amount of polyisobutylene (N50) and liquid paraffin (14%, the same as the prescription) and put them into the mixing pot. Set the oil bath to 170°C and the speed to 30 rpm and stir until the colloidal matrix is ​​visually melted and homogeneous. The material temperature is 120°C to 140°C.

[0080] (2) Add styrene-isoprene-styrene block copolymer and liquid paraffin (22%) to the mixing pot, set the oil bath to 160°C, and stir at 30 rpm until visually completely melted, with the material temperature at 130°C to 150°C.

[0081] (3) Add hydrogenated rosin glycerol ester and polyethylene glycol 20000 to the mixing pot, set the oil bath temperature to 160°C, and stir at 30 rpm until visually completely melted, with the material temperature at 120°C to 140°C.

[0082] (4) Preparation of the main drug mixture: Add API (compound 1 in free base form) to liquid paraffin (6%) and stir until visually dispersed.

[0083] (5) Preparation of menthol and polyethylene glycol 400 solution: Add the weighed menthol to polyethylene glycol 400, set the water bath to 40°C and stir until the menthol is completely dissolved.

[0084] (6) Add the main drug mixture to the mixing pot, set the oil bath temperature to 150°C, set the speed to 30 rpm and stir until visually uniform, and the material temperature is 110°C to 130°C.

[0085] (7) Add the mixture of menthol and polyethylene glycol 400 to the mixing pot, set the oil bath temperature to 150°C, set the speed to 30 rpm and stir until visually uniform, and the material temperature is 110°C to 130°C.

[0086] (8) Vacuuming: Set the rotation speed to 8 rpm, set the oil bath temperature to 150°C, vacuum for 10 minutes, and observe for large air bubbles that are not visible to the naked eye.

[0087] (9) Transfer the colloid to the liquid receiving plate of the hot melt coating machine for coating. Set the following coating parameters: composite roller 380°C, liquid receiving plate 140°C, support roller 140°C, coating roller 140°C. Coat with a size of 10cm×14cm and a paste content of 2.0g±0.2g. After cutting, pack it into a polyester / aluminum / polyethylene composite bag and seal it for storage.

[0088] Example 2

[0089] Preparation process: (1) Weigh out the prescribed amount of polyisobutylene (N50) and liquid paraffin (14%) and put them into the mixing pot. Set the oil bath to 170°C and the speed to 30 rpm. Stir until the colloidal matrix is ​​visually melted and homogeneous, and the material temperature is 120°C to 140°C.

[0090] (2) Add styrene-isoprene-styrene block copolymer and liquid paraffin (24%) to the mixing pot, set the oil bath to 160°C, and stir at 30 rpm until visually completely melted, with the material temperature at 130°C to 150°C.

[0091] (3) Add hydrogenated rosin glycerol ester and terpene resin to the mixing pot, set the oil bath temperature to 160°C, and stir at 30 rpm until visually completely melted, with the material temperature at 120°C to 140°C.

[0092] (4) Add the main drug, liquid paraffin (7%), cromiton and menthol to the mixing pot, set the oil bath temperature to 150°C, set the speed to 30 rpm and stir until visually uniform, and the material temperature is 110°C to 130°C.

[0093] (5) Vacuuming: Set the rotation speed to 8 rpm, set the oil bath temperature to 150°C, vacuum for 10 minutes, and observe for large air bubbles that are not visible to the naked eye.

[0094] (6) Transfer the colloid to the receiving plate of the hot melt coating machine for coating. Set the following coating parameters: composite roller 380°C, receiving plate 140°C, support roller 140°C, coating roller 140°C. Coat with a size of 10cm×14cm and a paste content of 2.0g±0.2g. After cutting, pack it into a polyester / aluminum / polyethylene composite bag and seal it for storage.

[0095] Example 3

[0096] Preparation process: (1) Weigh out the prescribed amount of polyisobutylene (N50) and liquid paraffin (14%) and put them into the mixing pot. Set the oil bath to 170°C and the speed to 30 rpm. Stir until the colloidal matrix is ​​visually melted and homogeneous, and the material temperature is 120°C to 140°C.

[0097] (2) Add styrene-isoprene-styrene block copolymer and liquid paraffin (24%) to the mixing pot, set the oil bath to 160°C, and stir at 30 rpm until visually completely melted, with the material temperature at 130°C to 150°C.

[0098] (3) Add hydrogenated rosin glycerol ester and terpene resin to the mixing pot, set the oil bath temperature to 160°C, and stir at 30 rpm until visually completely melted, with the material temperature at 120°C to 140°C.

[0099] (4) Add the main ingredient, liquid paraffin (7%), isopropyl myristate and menthol to the mixing pot, set the oil bath temperature to 150°C, set the speed to 30 rpm and stir until visually uniform, and the material temperature is 110°C to 130°C.

[0100] (5) Vacuuming: Set the rotation speed to 8 rpm, set the oil bath temperature to 150°C, vacuum for 10 minutes, and observe for large air bubbles that are not visible to the naked eye.

[0101] (6) Transfer the colloid to the receiving plate of the hot melt coating machine for coating. Set the following coating parameters: composite roller 380°C, receiving plate 140°C, support roller 140°C, coating roller 140°C. Coat with a size of 10cm×14cm and a paste content of 2.0g±0.2g. After cutting, pack it into a polyester / aluminum / polyethylene composite bag and seal it for storage.

[0102] Example 4

[0103] Preparation process: (1) Weigh out the prescribed amount of polyisobutylene (N50) and liquid paraffin (14%) and put them into the mixing pot. Set the oil bath to 170°C and the speed to 30 rpm. Stir until the colloidal matrix is ​​visually melted and homogeneous, and the material temperature is 120°C to 140°C.

[0104] (2) Add styrene-isoprene-styrene block copolymer, BHT and liquid paraffin (28%) to the mixing pot, set the oil bath to 160°C, and stir at 30 rpm until visually completely melted, with the material temperature at 130°C to 150°C.

[0105] (3) Add terpene resin to the mixing pot, set the oil bath temperature to 160°C, and stir at 30 rpm until it is visually completely melted. The material temperature is 120°C to 140°C.

[0106] (4) Add the main drug, polyethylene glycol 20000 and menthol to the mixing pot, set the oil bath temperature to 150°C, set the speed to 30 rpm and stir until visually uniform, and the material temperature is 110°C to 130°C.

[0107] (5) Vacuuming: Set the rotation speed to 8 rpm, set the oil bath temperature to 150°C, vacuum for 10 minutes, and observe for large air bubbles that are not visible to the naked eye.

[0108] (6) Transfer the colloid to the receiving plate of the hot melt coating machine for coating. Set the following coating parameters: composite roller 380°C, receiving plate 140°C, support roller 140°C, coating roller 140°C. Coat with a size of 10cm×14cm and a paste content of 2.0g±0.2g. After cutting, pack it into a polyester / aluminum / polyethylene composite bag and seal it for storage.

[0109] Examples 5-9:

[0110] Preparation process: The preparation process is the same as in Example 3 (details omitted).

[0111] Examples 10-12:

[0112] Preparation process: The preparation process is the same as in Example 3 (details omitted).

[0113] The transdermal, adhesive, and stability tests were conducted on the patch containing compound 1 of this invention. 1. In vitro transdermal experiment In vitro skin permeability studies of hairless rats were conducted using a transdermal absorption assay apparatus. A 0.01 mol / L phosphate-buffered saline solution was injected into the receiving chamber of the vertical diffusion cell of the transdermal absorption assay apparatus as the receiving solution, and stirred with a magnetic stirrer. The temperature of the receiving solution was maintained at approximately 32°C throughout the experiment. Skin from male hairless rats (HWY / Slc, SPF, 5 weeks old) was taken from their abdomens and stored at -80°C until use. After thawing, the hairless rat skin was shaped into 25 mm diameter circles. Each formulation was shaped into a 13 mm diameter circle, applied to the center of the hairless rat skin, and then placed on a unit of the transdermal absorption assay apparatus to begin the experiment. The receiving solution was collected at 3, 6, 9, 12, 20, and 24 hours after the start of the experiment, and the API and metabolites (degradation products) in the receiving solution were determined by HPLC. Unless otherwise stated, examples were conducted with n=4.

[0114]

[0115] The data in the table show that the hot-melt compound 1 transdermal patch has good transdermal properties, with a cumulative permeation of 986 µg / cm² over 24 hours for the three samples. The presence of a penetration enhancer in the formulation significantly increases the permeation.

[0116]

[0117] The data in the table show that as the proportion of API in the prescription increases, the permeation of Compound 1 transdermal patch gradually increases.

[0118] 2. Viscosity test The sample is placed at a temperature of 18~25℃ and a relative humidity of 40%~70% for more than 2 hours. After removing the cover, the steel ball is used to determine the adhesion of the plaster according to the first method (General Chapter 0952 of Part IV of Chinese Pharmacopoeia 2025). The angle of the inclined plate is 30° with a 1cm gap in the middle. The steel ball should stay on the adhesive surface.

[0119] Result determination: If all three steel balls adhered to by the three test samples are of the largest ball size, or if two of them are of the largest ball size and the third ball size is only one size smaller, the test is considered compliant. If one of the test samples is of the largest ball size and the other two ball sizes are only one size smaller, three more samples should be tested. If all three samples can adhere to the largest ball size, the test is considered compliant.

[0120] The test results are as follows:

[0121] According to the rolling ball data, the adhesion of samples in Examples 1-9 was generally good. Samples with a higher API content showed reduced adhesion. Furthermore, the proportion of matrix and tackifier in the formulation affected adhesion. The colloid prepared in Example 10 was too thin and lacked sufficient viscosity; the colloid prepared in Example 11 was too viscous, too hard, and had poor flowability, affecting the stability of subsequent coating processes. The colloid prepared in Example 12 was too viscous and had high viscosity, resulting in poor flowability. Therefore, the adhesion of Examples 10-12 was unsatisfactory and unsuitable for use as hot melt adhesives.

[0122] 3. Drug stability test The stability of Examples 1-9 was investigated after being placed at 40°C for 10 days and 30 days, respectively. The results are as follows:

[0123]

[0124]

[0125] Note: The dissolution time in the table is 18h; the cumulative permeation time is 24h.

[0126] The dissolution rate determination was performed as follows: The second method (paddle method) of Dissolution and Release Determination Method 0931 of the Pharmacopoeia of the People's Republic of China was used. Dissolution medium: A suitable buffer salt solution (or purified water / 0.9% sodium chloride solution, which can be supplemented according to the formulation) with a volume of 900 mL was used. Temperature conditions: The medium temperature was kept constant at 37±0.5℃. Stirring speed setting: The stirring paddle speed was set to 50 r / min. Sampling time: Samples were taken at fixed points at 18 hours, with a sample volume of 5 mL, and an isothermal blank dissolution medium of equal volume was added simultaneously. Sample processing: The extracted dissolution solution was filtered through a filter membrane, and the filtrate was used as the test sample solution. Detection calculation: The drug content in the test solution was determined by high performance liquid chromatography (HPLC). The dissolution amount per tablet was calculated using the external standard method and converted into a percentage relative to the labeled amount, which is the dissolution rate result.

[0127] As shown in the table above, the drug content of Examples 1-9 remained within ±2% after being placed at 40℃ for 30 days, with no significant degradation or decrease in content, indicating good chemical stability. Furthermore, the samples showed no sustained decrease or significant fluctuations within 40℃ for 30 days, demonstrating stable release behavior without any sudden release or slowed release. Moreover, the cumulative permeation amount over 24 hours for Examples 1-9 remained within ±5% within 30 days, with no sustained decrease or significant fluctuations, indicating stable transdermal delivery capability and that the skin permeability of the formulation was not affected by high-temperature conditions.

[0128] The embodiments of this application have been described above, but this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A hot-melt adhesive patch, the patch comprising an adhesive layer, characterized in that, The adhesive layer comprises a drug and a matrix, wherein the drug is a compound of formula (1) or a pharmaceutically acceptable salt thereof.

2. The hot-melt patch according to claim 1, characterized in that, The pharmaceutically acceptable salt of the compound shown in formula (1) is an acid addition salt of the compound shown in formula (1) with monocarboxylic acids such as acetic acid, propionic acid, and butyric acid, or dicarboxylic acids such as oxalic acid, malonic acid, fumaric acid, succinic acid, and maleic acid, or hydroxycarboxylic acids such as hydroxyacetic acid, lactic acid, malic acid, citric acid, and tartaric acid, or alkyl sulfonic acids such as carbonic acid, methanesulfonic acid, and ethanesulfonic acid, or organic acids such as amino acids such as glutamine, or an acid addition salt of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

3. The hot-melt patch according to claim 2, characterized in that, The matrix is ​​selected from urethanes, acrylics, styrene, and olefins, preferably styrene-based matrices, and more preferably styrene-based block copolymers.

4. The hot-melt patch according to claim 3, characterized in that, The adhesive layer further comprises at least one of a softener, a tackifier, an antioxidant, a penetration enhancer, a pH adjuster, an anti-irritant, and a solubilizer.

5. The hot-melt patch according to claim 4, characterized in that, The softener is selected from one or more of petroleum, silicone oil, liquid rubber, high molecular weight fatty acids, high molecular weight fatty acid esters, polyols, or vegetable oils. The petroleum includes one or more of paraffin oil, aromatic oil, petroleum resin, petrolatum, or liquid paraffin.

6. The hot-melt adhesive patch according to claim 5, characterized in that, The tackifier is selected from one or more of rosin resin, petroleum resin, terpene resin, polyterpene resin, phenol resin, terpene phenol resin or xylene resin; The rosin resin includes one or more of rosin ester, hydrogenated rosin, glycerol rosin ester, hydrogenated rosin glycerol ester, rosin acid, or polymerized rosin.

7. The hot-melt patch according to claim 6, characterized in that, The penetration enhancer is selected from one or more of the following: clomiphene, azone, menthol, N-methylpyrrolidone, oleic acid, eucalyptus oil, and isopropyl myristate.

8. The hot-melt patch according to any one of claims 1 to 7, characterized in that, The adhesive layer comprises, by weight percentage: 0.5wt%~30wt% of drug, 8wt%~66wt% of matrix, 10wt%~88wt% of softener and 1wt%~30wt% of tackifier; and further, by weight percentage: 5wt%~15wt% of drug, 15wt%~38wt% of matrix, 45wt%~68wt% of softener, 5wt%~18wt% of tackifier and 0.5wt%~5wt% of penetration enhancer.

9. The method for preparing the hot-melt patch according to any one of claims 1 to 8, characterized in that, The process includes the following steps: mixing, heating and melting the matrix, softener, drug, tackifier and penetration enhancer, and stirring evenly to obtain a paste; uniformly applying the paste to the backing layer, then bonding it to the protective layer, and finally cutting it into a suitable size to obtain a hot-melt patch.

10. Use of the hot-melt patch of any one of claims 1 to 8, or the hot-melt patch obtained by the preparation method of claim 9, in a medicament for treating fever, analgesia, and inflammation.

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