Gel plaster composition based on epoxy cross-linking agent and preparation method thereof

Abstract

The invention discloses a gel plaster composition based on an epoxy cross-linking agent. The gel plaster composition comprises the epoxy cross-linking agent and a cross-linking framework material, the epoxide cross-linking agent can form an ether bond with the cross-linking framework material; the epoxide cross-linking agent is glyceryl ether, and the molecule of the epoxide cross-linking agent contains two or more epoxy groups; the cross-linked framework material contains carboxyl and comprises one or two of polyacrylic acid and sodium carboxymethyl cellulose; the invention also comprises a preparation method of the gel plaster composition based on the epoxy cross-linking agent. The gel plaster composition disclosed by the invention adopts the epoxide cross-linking agent, and the required curing time is shortened to be within 1 / 5 of that of a metal ion cross-linking agent under the condition of the same dosage; the adhesive is a semi-solid after conventional curing, has good adhesion and stable physical properties, and in a stability test of 6-month acceleration and 24-month long term, the adhesive force and the release curve are basically unchanged.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to a gel patch composition of an epoxy crosslinking agent and its preparation method. Background Technology

[0002] Gel patches, also known as "patch patches," have become an important dosage form in modern transdermal drug delivery systems due to their significant advantages such as large drug loading capacity, good breathability, strong moisturizing properties, good skin compatibility, comfortable and convenient use, and low sensitivity. They are widely used in various fields such as analgesia and anti-inflammation, promoting blood circulation and removing blood stasis, hormone replacement therapy, and treatment of nervous system diseases.

[0003] Packaged gel patch products consist of a backing cloth, an anti-adhesive layer, and the patch between the backing cloth and the anti-adhesive layer. The patch is an adhesive, semi-solid substance. When taking the medication, the patient needs to remove the anti-adhesive layer and then apply the patch to the treatment area. Currently, gel patches mainly use cross-linked matrices. The preparation process mainly includes steps such as paste preparation (also known as "refining"), coating and cutting, curing, and packaging. Paste preparation refers to the thorough and uniform mixing of all components into a paste. Coating refers to applying the prepared paste between the backing cloth and the anti-adhesive layer. During the coating process, the paste needs to maintain suitable fluidity to ensure uniform and smooth coating. Afterward, it is cut to an appropriate size. Curing refers to placing the cut patch under specific temperature and humidity conditions for a period of time, allowing the cross-linked backbone material and cross-linking agent in the patch to undergo a cross-linking reaction to form a molecular-level cross-linked network structure. This causes the paste to lose its fluidity and become manually peelable from the anti-adhesive layer, thus preventing displacement and dripping of the patch during storage, transportation, and use, and making it easier for patients to use. The release liner of gel patches that have not reached the curing endpoint cannot be easily removed.

[0004] The cross-linking reaction continues for a considerable period during the preparation, coating, curing, and even subsequent storage of the paste. This cross-linking reaction exhibits a rapid initial reaction followed by a slower subsequent reaction, and can be roughly divided into three stages: a rapid reaction stage, a slow reaction stage, and a termination stage. The rapid reaction stage typically refers to the early stages of paste refining, curing, and even storage, and the reaction rate varies depending on the composition. The slow reaction stage typically refers to the period from storage until the reaction terminates.

[0005] Existing technologies often employ chelation curing of high-valence metal ions with water-soluble polymers to achieve crosslinking. Essentially, this involves establishing connection points between multiple polymer chains through ionic or coordinate bonds, thereby forming a three-dimensional crosslinked network hydrogel structure with specific grid dimensions and mechanical properties. While hydrogel structures formed by metal ion crosslinking agents have advantages such as strong cohesion and good adhesion, these crosslinking agents suffer from two fundamental drawbacks that are difficult to overcome: slow crosslinking reaction rates and uneven crosslinking reactions.

[0006] Uneven cross-linking reaction leads to poor product stability and uncontrollable drug release. A slow cross-linking reaction rate results in excessively long curing times: to ensure complete reaction of the cross-linking agent and to allow the initially formed network structure to reach mechanical equilibrium and stability, traditional processes require a "curing" or "aging" process under specific environmental temperature and humidity conditions for several days, weeks, or even months after coating and molding. For example, the preparation of loxoprofen sodium gel patch in CN202010651705.5 requires curing at 20-30℃ for 4-6 days; the curing process for lidocaine gel patch is even longer, requiring several weeks or even 1-2 months at 20-30℃.

[0007] Of course, to accelerate the cross-linking reaction rate and shorten the curing time, researchers have also tried curing at higher temperatures (such as 40°C or even higher). This technology can indeed significantly accelerate the cross-linking reaction rate, but high temperatures may not only accelerate the degradation of drugs in the patch, but also accelerate the aging of the patch, thus affecting the quality of the patch product. The slow cross-linking reaction rate of gel patches results in excessively long production cycles, and maintaining a constant temperature and humidity curing environment consumes a lot of resources; currently, there is no good solution. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a gel patch composition based on an epoxy crosslinking agent with fast crosslinking speed and its preparation method.

[0009] The technical solution adopted by the present invention to solve its technical problem is as follows: a gel plaster composition based on an epoxy crosslinking agent, comprising an epoxy crosslinking agent and a crosslinking backbone material; the epoxy crosslinking agent is capable of forming ether bonds with the crosslinking backbone material; the gel plaster composition has viscous properties after curing and is semi-solid; The epoxide crosslinking agent is a glycerol ether, and the molecule contains two or more epoxy groups; The cross-linked backbone material contains carboxyl groups, including one or two of polyacrylic acid and sodium carboxymethyl cellulose. The epoxide crosslinking agent accounts for 0.01% to 5% of the mass of the gel patch composition; The mass ratio of the epoxide crosslinking agent to the crosslinking backbone material is 1:0.8~1500.

[0010] Preferably, the epoxide crosslinking agent includes one or more of polyglycerol glycidyl ether, polyglycerol polyglycidyl ether, pentaerythritol glycidyl ether, and polyethylene glycol diglycidyl ether.

[0011] Preferably, it further includes a tackifier; the tackifier accounts for less than 40% of the mass of the gel patch composition.

[0012] Preferably, the thickener comprises one or more of polyacrylic acid, gelatin, sodium carboxymethyl cellulose, acrylic acid grafted starch, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and polyvinyl alcohol.

[0013] Preferably, it further includes a crosslinking regulator; the crosslinking regulator includes disodium edetate.

[0014] Preferably, the pH value of the gel patch composition is 4 to 7.

[0015] Preferably, it contains one or two active pharmaceutical ingredients selected from local anesthetics and nonsteroidal anti-inflammatory drugs.

[0016] Preferably, it contains one or more active pharmaceutical ingredients selected from lidocaine, loxoprofen sodium, and ketoprofen.

[0017] Preferably, the epoxide crosslinking agent accounts for 0.02% to 1% of the mass of the gel patch composition.

[0018] Preferably, the mass ratio of the epoxide crosslinking agent to the crosslinking backbone material is 1:5 to 300.

[0019] Based on the same inventive concept, the present invention also provides a method for preparing a gel plaster composition based on an epoxy crosslinking agent: first, the raw and auxiliary materials other than the epoxy crosslinking agent are dissolved and mixed together, and then the epoxy crosslinking agent is added and mixed evenly to obtain a gel plaster composition.

[0020] The present invention has the following beneficial effects: (1) The gel patch composition of the present invention uses an epoxide crosslinking agent, which can significantly accelerate the maturation of the patch compared with traditional crosslinking agents. The required maturation time under the same dosage is shortened to less than 1 / 5 of that using metal ion crosslinking agents. (2) The gel plaster composition of the present invention is a semi-solid after conventional curing, with good adhesion and stable physical properties. In the accelerated stability test of 6 months and long-term stability test of 24 months, the adhesion force and release curve remain basically unchanged; while the traditional metal ion crosslinking agent will have large fluctuations.

[0021] In addition to the objectives, features, and advantages described above, the present invention has other objectives, features, and advantages. The invention will now be described in further detail with reference to the accompanying drawings. Attached Figure Description

[0022] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1This is an average cumulative release curve of the products of Embodiment 1.3 and Comparative Example 1.2 after being stored under different conditions. Detailed Implementation

[0023] To make the objectives, solutions, and beneficial technologies of this invention clearer, the invention will be further described in detail below with reference to embodiments and accompanying drawings. It should be noted that the embodiments described in this specification are merely illustrative of the invention and are not intended to limit the invention.

[0024] For simplicity, this paper only explicitly discloses some numerical ranges. However, any lower limit can be combined with any upper limit to form an undefined range; and any lower limit can be combined with other lower limits to form an undefined range, just as any upper limit can be combined with any other upper limit to form an undefined range. Furthermore, although not explicitly stated, every point or individual value between the endpoints of a range is included within that range. Therefore, each point or individual value can serve as its own lower or upper limit and be combined with any other point or individual value, or with other lower or upper limits, to form an undefined range.

[0025] In this description, it should be noted that, unless otherwise stated, "above" and "below" include the stated number, "multiple" in "one or more" means two or more, and "more than" in "one or more" means two or more.

[0026] An embodiment of the present invention provides a gel patch composition based on an epoxy crosslinking agent, comprising an epoxy crosslinking agent and a crosslinking backbone material; the epoxy crosslinking agent is capable of forming ether bonds with the crosslinking backbone material; the gel patch composition becomes viscous and semi-solid after curing; The epoxide crosslinking agent is a glycerol ether, and the molecule contains two or more epoxy groups; The cross-linked backbone material contains carboxyl groups, including one or two of polyacrylic acid and sodium carboxymethyl cellulose. The epoxide crosslinking agent accounts for 0.01% to 5% of the mass of the gel patch composition; The mass ratio of the epoxide crosslinking agent to the crosslinking backbone material is 1:0.8~1500.

[0027] The gel patch composition is applied to a backing material using conventional processes, covered with an anti-adhesive layer, and then cured to obtain the gel patch product. Both application and curing can be performed using conventional methods.

[0028] This invention uses epoxy-based crosslinking agents as the core crosslinking agent, solving the problems of long curing time (≥120 hours) and continuous crosslinking during storage caused by metal ion crosslinking agents (such as aluminum hydroxide and aluminum hydroxide), which leads to unstable physical properties of the product. The reaction mechanism between the crosslinking agent and the crosslinking backbone material in this invention is essentially a nucleophilic addition reaction between the epoxy groups and the polymer functional groups after ring opening. Epoxide-based crosslinking agents react with the carboxyl groups of the crosslinking backbone material through multiple epoxy groups; one epoxy molecule contains two or more epoxy groups, which can simultaneously connect multiple polymer chains: through repeated crosslinking, the linear polymer forms a through-linked ether bond network, endowing the gel with high water retention, cohesive strength, and viscoelasticity. It can significantly shorten the curing time, and the physical properties of the plaster composition are stable after curing, with essentially unchanged adhesion and a stable release curve. This technology significantly improves production efficiency and ensures product stability during storage, and is suitable for gel-based drug delivery formulations such as lidocaine, ketoprofen, and loxoprofen sodium.

[0029] The epoxy crosslinking agent of this invention is generally used in the prior art to prepare thermosetting materials. Thermosetting refers to a polymer material that cannot be melted back into a flowable state after curing. Thermosetting materials made with epoxy crosslinking agents have the characteristics of high strength and high hardness, but cannot maintain a viscous state for a long time after initial curing. This does not meet the basic requirements of a semi-solid state and certain adhesive properties required for gel patches, which is why epoxy crosslinking agents have not been considered for use in gel patches for a long time.

[0030] In embodiments of the present invention, the epoxide crosslinking agent includes one or more of polyglycerol glycidyl ether, polyglycerol polyglycidyl ether, pentaerythritol glycidyl ether, and polyethylene glycol diglycidyl ether.

[0031] In embodiments of the present invention, the gel patch composition further includes a tackifier; the tackifier accounts for less than 40% of the mass of the gel patch composition. The epoxide crosslinking agent can form a viscous semi-solid after mixing and maturing with the crosslinking backbone material, and further tackifiers can be added to control the viscosity of the product.

[0032] In embodiments of the present invention, the thickener includes one or more of polyacrylic acid, gelatin, sodium carboxymethyl cellulose, acrylic acid grafted starch, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and polyvinyl alcohol.

[0033] In embodiments of the present invention, the gel patch composition further includes a crosslinking regulator; the crosslinking regulator includes disodium edetate.

[0034] In embodiments of the present invention, the pH value of the gel patch composition is 4-7. The pH value requirement mainly stems from the need for the gel patch composition to come into contact with the skin. If the pH value does not meet the requirements, it can be adjusted using conventional pH adjusters. In some embodiments of the present invention, the pH adjuster is an acidic pH adjuster (tartaric acid, citric acid) or an alkaline pH adjuster (arginine).

[0035] In embodiments of the present invention, the gel patch composition further includes a filler; the filler includes one or both of kaolin and titanium dioxide.

[0036] In embodiments of the present invention, the gel patch composition contains one or two of the active pharmaceutical ingredients of a local anesthetic and a nonsteroidal anti-inflammatory drug.

[0037] In embodiments of the present invention, the gel patch composition contains one or more of the following pharmaceutical active ingredients: lidocaine, loxoprofen sodium, and ketoprofen.

[0038] In embodiments of the present invention, the epoxide crosslinking agent accounts for 0.02% to 1% of the mass of the gel patch composition.

[0039] In an embodiment of the present invention, the mass ratio of the epoxide crosslinking agent to the crosslinking backbone material is 1:5 to 300.

[0040] In some embodiments of the present invention, the solvent accounts for less than 70% of the mass of the gel patch composition.

[0041] In some embodiments of the present invention, the gel patch composition contains glycerin.

[0042] This invention also provides a method for preparing a gel patch composition based on an epoxy crosslinking agent: first, the raw materials and excipients, except for the epoxy crosslinking agent, are dissolved and mixed together, then the epoxy crosslinking agent is added and mixed thoroughly to obtain the gel patch composition. "Raw materials and excipients" is a common term in the art, referring to active ingredients and excipients.

[0043] In some embodiments of the present invention, the raw materials and excipients are first prepared into components A, B, C, and D; wherein component A contains dissolved active pharmaceutical ingredients; component B contains dissolved crosslinking regulators and some thickeners; component C contains dissolved epoxide crosslinking agents; and component D is a glycerol suspension containing crosslinking backbone materials and some thickeners. After mixing components A, B, and D, component C is added and mixed thoroughly. The pH value of the mixture is controlled at 4-7 to obtain a gel patch composition.

[0044] Example The following examples describe the disclosure of this invention in more detail. These examples are merely illustrative, as various modifications and variations will be apparent to those skilled in the art within the scope of this disclosure. Unless otherwise stated, all parts, percentages, and ratios reported in the following examples are based on weight. Unless otherwise stated, all reagents used in the examples are available commercially or synthesized using conventional methods and are ready for use without further processing. Unless otherwise stated, all instruments used in the examples are available commercially.

[0045] The polyglycerol glycidyl ether appearing in the examples is from Guangdong Xinyuan Technology Development Co., Ltd.

[0046] The polyglycerol polyglycidyl ether appearing in the examples is from Shanghai Pincheng Pharmaceutical Technology Co., Ltd.

[0047] The partially neutralized sodium polyacrylate mentioned in the examples was purchased from Shanghai Pincheng Pharmaceutical Technology Co., Ltd., with a sodium acrylate:acrylic acid ratio of 70:30 (molar amount).

[0048] The following are examples of gel patches with lidocaine, loxoprofen sodium, and ketoprofen as their active pharmaceutical ingredients; I. Specific Examples of Lidocaine Gel Patch 1.1 Composition and preparation of lidocaine gel patch composition 1.1.1 The composition of the lidocaine gel patch compositions of each embodiment and reference example is shown in Table 1-1; the composition of the lidocaine gel patch compositions of the comparative examples is shown in Table 1-2; " / " in the table indicates that it is not used.

[0049] Table 1-1 Composition of lidocaine gel patch compositions in examples and reference examples

[0050] Examples 1.1-1.5 and Reference Example 1.1 investigated different proportions of polyglycerol glycidyl ether (5%, 0.5%, 0.2%, 0.05%, 0.02%, 0.002%). Example 1.7 used another epoxide crosslinking agent (polyglycerol glycidyl ether). The formulation of Example 1.8 used two epoxide crosslinking agents. Compared with the examples, Comparative Examples 1.1-1.8 used metal ion crosslinking agents (aluminum hydroxyl, aluminum hydroxide) in different proportions (0.5%, 0.2%, 0.05%, 0.02%). The formulation of Comparative Example 1.9 did not use any crosslinking agent.

[0051] In each formulation, the active pharmaceutical ingredient is lidocaine; the cross-linking matrix material includes partially neutralized sodium polyacrylate; the cross-linking regulator includes disodium edetate; and polyacrylic acid, gelatin, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, sodium carboxymethyl cellulose, and polyvinyl alcohol act as thickeners.

[0052] Table 1-2 Composition of comparative lidocaine gel patch compositions

[0053] 1.1.2 The lidocaine gel patches of each embodiment, reference example, and comparative example were prepared according to the following method: (1) First, prepare the raw materials and auxiliary materials into components A, B, C, and D: Component A: Dissolve the active pharmaceutical ingredient in a portion of the solvent (propylene glycol) by stirring to obtain Component A; Component B: Take sorbitol, crosslinking regulator (disodium edetate), pH regulator (tartaric acid), gelatin, polyvinyl alcohol, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and polyacrylic acid, and dissolve them in water by stirring to obtain component B; Component C: Add the crosslinking agent to a portion of the solvent (propylene glycol) and stir to dissolve, thus obtaining component C; Component D: Take the cross-linked backbone material (partially neutralized sodium polyacrylate), kaolin, and sodium carboxymethyl cellulose, add them to glycerol and stir until they are mixed evenly to form a glycerol suspension, thus obtaining component D; (2) Add component A and component B to component D and mix and stir. Then add component C and mix evenly. The pH value of the mixture is measured to be in the range of 4 to 7. This is the lidocaine gel patch composition.

[0054] The obtained lidocaine gel patch composition is applied to a backing material and covered with an anti-adhesive layer to obtain a lidocaine gel patch product.

[0055] 1.2 Effect Evaluation 1.2.1 Examination of the peeling condition of the drug-containing layer and the anti-adhesion layer The lidocaine gel patch products of each embodiment, reference example and comparative example were aged at 30°C for different times (12h, 24h, 72h, 96h, 120h, 1 week, 2 weeks, 3 weeks and 4 weeks) to investigate the separation of the drug-containing layer and the anti-adhesive layer.

[0056] Test method: Take one test sample, remove the anti-adhesive layer, and examine the difficulty of peeling the medicated layer and the anti-adhesive layer to preliminarily assess the cross-linking of the ointment; if the ointment and the anti-adhesive layer stick together during peeling, it is considered that it cannot be peeled off smoothly, indicating poor cross-linking effect and poor maturation degree; the easier it is to peel off, the better the cross-linking degree and the better the maturation degree.

[0057] The results are shown in Table 2.

[0058] Table 2. Peeling behavior of lidocaine gel patch products in various examples, reference examples, and comparative examples.

[0059] The results show that the use of epoxide crosslinking agents significantly optimizes the peeling process and achieves a better degree of crosslinking compared to traditional metal ion crosslinking agents. In Reference Example 1.1, even with only 0.002% of the epoxide crosslinking agent in the gel patch composition, the peeling requirement was met within 72 hours; with a larger amount of epoxide crosslinking agent, the peeling requirement was met within 12 hours. Comparative Example 1.9, without crosslinking agent, still failed to peel after 4 weeks. The shortest peeling time for Comparative Examples 1.1-1.8 using traditional metal ion crosslinking agents was 72 hours, with Comparative Example 1.8 (0.02%) failing to peel after 4 weeks (correspondingly, Example 1.5 (0.02% epoxide crosslinking agent) met the peeling requirement within 12 hours). This indicates that the gel patch with epoxide crosslinking agent matures significantly faster than that using traditional metal ion crosslinking agents, requiring less epoxide crosslinking agent to achieve the same peeling effect.

[0060] 1.2.2 Examination of Initial Viscosity Test Results The initial tack of each lidocaine gel patch product was determined during the stability study.

[0061] Test method: Take one sample and place it at 18~25℃ and relative humidity 40%~70% for at least 2 hours. Remove the plastic film and test according to the adhesion test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0952, Method I). The angle of the inclined plate is 45°, and record the residence time of the largest steel ball on the adhesive surface, which should be no less than 5 seconds.

[0062] Table 3 shows the test results of some representative embodiments and comparative examples.

[0063] Table 3. Initial tack test results of lidocaine gel patch products in the examples and some comparative examples.

[0064] During testing, it was found that the paste in Reference Example 1.1 was too soft and prone to displacement; initial tack was not tested. In the stability studies using epoxide crosslinking agents in Examples 1.2-1.5, the initial tack of the samples remained relatively stable after 6 months of accelerated testing and 24 months of long-term testing. The paste in Example 1.1 was too hard; after 6 months of accelerated testing and 24 months of long-term testing, the initial tack of the sample decreased, presumably due to excessive use of epoxide crosslinking agent and over-crosslinking. The initial tack test results of Example 1.1 were close to those of the comparative examples using traditional metal ion crosslinking agents.

[0065] 1.2.3 In vitro release test The cross-linking reaction of gel patch products continues until the reactants (cross-linking matrix material or cross-linking agent) are depleted, that is, the chemical reaction reaches equilibrium or endpoint. Even after the product has matured, the reaction may continue slowly for months, years or even until the end of the product's shelf life. The three-dimensional network structure formed by the cross-linking reaction will affect the rate and extent of drug release from the patch, resulting in differences in the average cumulative release rate in the initial stage, the middle of the shelf life and the end of the shelf life, which directly affects the product's efficacy.

[0066] Lidocaine gel patches from Examples 1.3, 1.4, 1.2, and 1.6 were selected for in vitro release tests to examine their release after storage under different conditions. The average cumulative release rate is shown in Table 4, and the fluctuation of the average cumulative release rate is shown in Table 5. The units for the average cumulative release rate and the difference between the average cumulative release rates in the tables are %. The average cumulative release rates of the products from Examples 1.3 and 1.2 after storage under different conditions are shown in Table 5. Figure 1 .

[0067] Table 4. Average cumulative release rates of the gel patch products in Examples 1.3, 1.4 and Comparative Examples 1.2, 1.6

[0068] Dissolution and release were determined according to the method described in the Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method IV. The sample was cut into 2cm diameter circular slices, accurately weighed, and then pasted onto a mesh tray (3cm diameter) with the paste side facing upwards. The plastic film was then removed. 900mL of pH 4.0 sodium acetate buffer (5.44g of sodium acetate trihydrate was dissolved in 900mL of water, the pH was adjusted to 4.0 by adding glacial acetic acid, and diluted to 1000mL with water) was used as the dissolution medium. The dissolution was performed at 50 rpm. After 0.5h, 2h, and 6h, 5mL of the dissolution solution was collected, and immediately replenished with the same volume and temperature (32±0.5℃) of dissolution medium.

[0069] Test solution: Take the dissolution solution at 0.5h, 2h and 6h respectively, filter it and take the filtrate.

[0070] Reference solution: Weigh approximately 17.5 mg of lidocaine reference standard accurately, place it in a 50 mL volumetric flask, add methanol to dissolve and dilute to the mark, shake well, accurately measure 1 mL, place it in a 20 mL volumetric flask, dilute to the mark with diluent, and shake well.

[0071] Chromatographic conditions: A column packed with octadecyl-bonded silica gel was used; the mobile phase was pH 8.0 phosphate buffer-acetonitrile (60:40); and the detection wavelength was 230 nm. Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid phase, determine the release rate, and calculate the average cumulative release rate.

[0072] As shown in Tables 4 and 5, all examples and comparative examples basically achieved complete release within 6 hours under various stability conditions; however, under accelerated and long-term conditions, the average cumulative release rate of Comparative Examples 1.2 and 1.6 was significantly reduced in the first 0.5 hours compared to day 0, with a difference between 10% and 15%, and the difference between the average cumulative release rate and the average cumulative release rate at 2 hours was between 5% and 10%; the release curves of Examples 1.3 and 1.4 remained stable and essentially unchanged under accelerated and long-term conditions. Figure 1 It can also be seen that the average cumulative release curves of the product in Example 1.3 after being stored under different conditions are highly consistent, while the average cumulative release of the product in Comparative Example 1.2 after a period of time is significantly different from that at 0 months.

[0073] Table 5. Average cumulative release fluctuations of the gel patch products in Examples 1.3, 1.4 and Comparative Examples 1.2, 1.6

[0074] 1.2.4 In vitro transdermal experiment Using pig skin as a barrier, in vitro transdermal tests were conducted on the freshly prepared and matured gel patch products of Examples 1.2, 1.4, 1.5, and 1.7. The results are shown in Table 6. The specific experimental method is as follows: Release conditions: LOGAN SYSTEM 918-12 transdermal diffusion instrument, physiological saline as the release medium, temperature 32℃, rotation speed 600 rpm. Skin material was 1-month-old Bama miniature pig skin, 0.6~0.8mm thick, cut into 3×3cm pieces, thawed in physiological saline for about 10 minutes, dried with filter paper, and fixed on the diffusion tank for at least 30 minutes to equilibrate. The gel patch with the cover removed was applied to the skin, and the stirring speed was 600 rpm. Sampling time points: 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours.

[0075] Chromatographic conditions: Octadecyl-bonded silica gel (Waters XTerra-PR18, 3.9×150mm, 5μm) or equivalent column was used as the stationary phase; 0.005mol / L phosphate buffer (4.85g / L potassium dihydrogen phosphate solution, pH adjusted to 8.0 with saturated sodium hydroxide solution)-acetonitrile (65:35) was used as the mobile phase; the detection wavelength was 230nm; the column temperature was 30℃; the injection volume was 20μL; and the flow rate was 1.0mL / min. The cumulative permeation % (i.e., the cumulative amount of lidocaine that permeated) was calculated.

[0076] Table 6. Cumulative lidocaine penetration of gel patch products in each embodiment.

[0077] The above results indicate that, in the in vitro transdermal absorption experiment, the drug release rate of each combination of lidocaine gel patch products increased at a relatively uniform rate over time.

[0078] II. Specific Examples of Loxoprofen Sodium Gel Patch 2.1 Composition and preparation of loxoprofen sodium gel patch composition 2.1.1 The composition of the loxoprofen sodium gel patch compositions in each embodiment and comparative example is shown in Table 7; " / " in the table indicates that it is not used.

[0079] Examples 2.1-2.3 investigated different proportions of polyglycerol polyglycidyl ether (0.65%, 0.31%, 0.025%). Comparative Examples 2.1-2.3, compared to the examples, used a metal ion crosslinking agent (aluminum hydroxide), with the usage proportions corresponding to those in Examples 2.1-2.3 (0.65%, 0.31%, 0.025%). Comparative Example 2.4 did not use any crosslinking agent.

[0080] In each formulation, the active pharmaceutical ingredient is loxoprofen sodium; the cross-linking matrix material includes partially neutralized sodium polyacrylate; the cross-linking regulator includes disodium edetate; sodium carboxymethyl cellulose, acrylic acid grafted starch 300, and methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion act as thickeners.

[0081] Table 7 Composition of the loxoprofen sodium gel patch compositions in each embodiment and comparative example

[0082] 2.1.2 The loxoprofen sodium gel patches of each embodiment and comparative example were prepared according to the following method: (1) First, prepare the raw materials and auxiliary materials into components A, B, C, and D: Component A: Dissolve the active pharmaceutical ingredient in water by stirring to obtain Component A; Component B: Take the crosslinking regulator (disodium edetate), pH regulator (tartaric acid), and methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and stir to dissolve them in water to obtain component B; Component C: Add crosslinking agent, polysorbate 80, and peppermint oil to cromite, stir to dissolve, and obtain component C; Component D: Take the cross-linked backbone material (partially neutralized sodium polyacrylate), sodium carboxymethyl cellulose, acrylic acid grafted starch 300, talc, and titanium dioxide, add them to glycerol and stir until they are mixed evenly to form a glycerol suspension, thus obtaining component D; (2) Add component A and component B to component D and mix and stir. Then add component C and mix evenly. The pH value of the mixture is measured to be in the range of 4 to 7, thus obtaining the loxoprofen sodium gel patch composition.

[0083] The obtained loxoprofen sodium gel patch composition was applied to a backing material and covered with an anti-adhesive layer to obtain the loxoprofen sodium gel patch product.

[0084] 2.2 Effect Evaluation 2.2.1 Examination of the peeling condition of the drug-containing layer and the anti-adhesion layer: Loxoprofen sodium gel patches from each example and comparative example were aged at 30°C for different times (12h, 24h, 72h, 96h, 120h, 1 week, 2 weeks, 3 weeks, 4 weeks) to investigate the separation of the drug-containing layer from the anti-adhesive layer.

[0085] Test method: Take one test sample, remove the anti-adhesive layer, and examine the difficulty of peeling the medicated layer and the anti-adhesive layer to preliminarily assess the cross-linking of the ointment; if the ointment and the anti-adhesive layer stick together during peeling, it is considered that it cannot be peeled off smoothly, indicating poor cross-linking effect and poor maturation degree; the easier it is to peel off, the better the cross-linking degree and the better the maturation degree.

[0086] The results are shown in Table 8. Table 8. Peeling performance of loxoprofen sodium gel patches in each example and comparative example.

[0087] The results showed that the gel patches using epoxide crosslinking agents met the peeling requirements within 12 hours; Comparative Example 2.4, without crosslinking agent, still failed to peel after 4 weeks. Comparative Examples 2.1-2.3, using traditional metal ion crosslinking agents, even Comparative Example 2.1 (0.65%) with a higher crosslinking agent concentration, required 120 hours for successful peeling; Comparative Examples 2.2 and 2.3, with even lower crosslinking agent concentrations, required even longer times. At the same concentration, the longer peeling time required with metal ion crosslinking agents indicates that the gel patches with epoxide crosslinking agents mature significantly faster than those using traditional metal ion crosslinking agents, requiring less epoxide crosslinking agent to achieve the same peeling effect.

[0088] 2.2.2 Examination of Initial Viscosity Test Results The initial tack of each loxoprofen sodium gel patch product was determined during the stability study.

[0089] Test method: Take one sample and place it at 18~25℃ and relative humidity 40%~70% for at least 2 hours. Remove the plastic film and test according to the adhesion test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0952, Method I). The angle of the inclined plate is 45°, and record the residence time of the largest steel ball on the adhesive surface, which should be no less than 5 seconds.

[0090] Table 9 shows the test results of some representative embodiments and comparative examples.

[0091] Table 9 Initial tack test results of loxoprofen sodium gel patches in the examples and some comparative examples

[0092] As can be seen from Examples 2.1 to 2.3, the samples using epoxide crosslinking agents showed little change in initial tack in the stability study and were able to maintain relative stability under both accelerated and long-term conditions; while the comparative examples 2.1 to 2.3 using metal ion crosslinking agents showed a significant decrease in initial tack during the stability test.

[0093] 2.2.3 In vitro release test Loxoprofen sodium gel patches from Examples 2.2 and 2.2 were selected as representatives for in vitro release tests to detect their release after storage under different conditions. The average cumulative release rate is shown in Table 10, and the fluctuation of the average cumulative release rate is shown in Table 11. The units for the average cumulative release rate and the difference between the average cumulative release rates in the tables are %.

[0094] Table 10. Average cumulative release of the gel patch products of Example 2.2 and Comparative Example 2.2

[0095] Take a sample and cut it into a circular slice with a diameter of 2.0 cm (equivalent to 2.24 mg of loxoprofen sodium). Weigh it accurately and attach the sample slice to a semi-permeable membrane cut with a diameter of 3 cm. Fix it on a vertical Franz diffusion cell equipped with a magnetic stirrer. The receiving medium is an acetate medium with a pH of 4.5. Take 5 mL of the receiving solution after 1 h, 3 h and 5 h respectively, and add the same volume of receiving medium at the same time.

[0096] Table 11. Average cumulative release fluctuation of the gel patch products in Example 2.2 and Comparative Example 2.2

[0097] The release study showed that, under accelerated and long-term conditions, Comparative Example 2.2 showed a significant decrease in the average cumulative release rate in the first hour compared to day 0, with the difference in average cumulative release rate between 10% and 15%, and the difference in average cumulative release rate in the first 3 hours between 8% and 12%. Under accelerated and long-term conditions, the release curve of Example 2.2 remained stable and essentially unchanged over the long term.

[0098] 2.2.4 In vitro transdermal experiment Using pig skin as a barrier, in vitro transdermal tests were conducted on the freshly prepared and matured loxoprofen sodium gel patches of Example 2.2 and Comparative Example 2.2 (matured for 12 hours in Example 2.2; matured for one week in Comparative Example 2.2). The results are shown in Table 12. The specific experimental method is as follows: Release conditions: LOGAN SYSTEM 918-12 transdermal diffusion instrument, physiological saline as the release medium, temperature 32℃, rotation speed 600 rpm. Sampling time points: 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours. Samples were measured, and the cumulative permeation percentage (i.e., the cumulative amount of loxoprofen sodium permeated) was calculated.

[0099] Table 12. Cumulative penetration of loxoprofen sodium in the gel patch products of Example 2.2 and Comparative Example 2.2

[0100] The above results indicate that the loxoprofen sodium gel patch provided by this invention exhibits essentially the same transdermal absorption effect as the currently mainstream loxoprofen sodium gel patches using metal ion crosslinking agents in in vitro transdermal absorption experiments. This invention significantly reduces the curing time while achieving the same effect, greatly improving production efficiency.

[0101] III. Specific Examples of Ketoprofen Gel Patches 3.1 Composition and preparation of ketoprofen gel patch composition 3.1.1 The composition of the ketoprofen gel patch compositions of each embodiment and comparative example is shown in Table 13; " / " in the table indicates that it is not used.

[0102] Examples 3.1-3.3 investigated different proportions of polyglycerol glycidyl ether (0.67%, 0.05%, 0.025%). Comparative Examples 3.1-3.3, compared to the examples, used a metal ion crosslinking agent (aluminum hydroxide), with the usage proportions corresponding to those in Examples 3.1-3.3 (0.67%, 0.05%, 0.025%). Comparative Example 3.4 did not use any crosslinking agent.

[0103] In each formulation, the active pharmaceutical ingredient is ketoprofen; the cross-linking matrix material includes partially neutralized sodium polyacrylate; the cross-linking regulator includes disodium edetate; and polyacrylic acid, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, polyvinyl alcohol, and gelatin act as thickeners.

[0104] Table 13 Composition of the ketoprofen gel patch compositions in each example and comparative example

[0105] 3.1.2 The ketoprofen gel patches of each embodiment and comparative example were prepared according to the following method: (1) First, prepare the raw materials and auxiliary materials into components A, B, C, and D: Component A: Dissolve the active pharmaceutical ingredient in a portion of the solvent (propylene glycol) by stirring to obtain Component A; Component B: Take the crosslinking regulator (disodium edetate), polyvinyl alcohol, gelatin, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and polyacrylic acid, and stir to dissolve them in water to obtain component B; Component C: Take avobenzone, hexyl laurate, and menthol, add them to cromite and stir to dissolve, then add the crosslinking agent and stir thoroughly to obtain component C; Component D: Take the cross-linked backbone material (partially neutralized sodium polyacrylate) and kaolin, add them to glycerol and stir until they are mixed evenly to form a glycerol suspension, thus obtaining component D; (2) Add component A and component B to component D and mix and stir. Then add component C and mix evenly. The pH value of the mixture is measured to be in the range of 4 to 7, and the ketoprofen gel patch composition is obtained.

[0106] The obtained ketoprofen gel patch composition was coated onto a backing material and covered with an anti-adhesive layer to obtain the ketoprofen gel patch product.

[0107] 3.2 Effect Evaluation 3.2.1 Examination of the peeling condition of the drug-containing layer and the anti-adhesion layer: The ketoprofen gel patch products of each embodiment and comparative example were aged at 30°C for different times (12h, 24h, 72h, 96h, 120h, 1 week, 2 weeks, 3 weeks, 4 weeks) to investigate the separation of the drug-containing layer and the anti-adhesive layer.

[0108] Test method: Take one test sample, remove the anti-adhesive layer, and examine the difficulty of peeling the medicated layer and the anti-adhesive layer to preliminarily assess the cross-linking of the ointment; if the ointment and the anti-adhesive layer stick together during peeling, it is considered that it cannot be peeled off smoothly, indicating poor cross-linking effect and poor maturation degree; the easier it is to peel off, the better the cross-linking degree and the better the maturation degree.

[0109] The results are shown in Table 14. Table 14 Peeling characteristics of ketoprofen gel patches in each example and comparative example

[0110] The results showed that the gel patches using epoxide crosslinking agents met the peeling requirements within 12 hours; Comparative Example 3.4, without crosslinking agent, still failed to peel after 4 weeks. Comparative Examples 3.1-3.3, using traditional metal ion crosslinking agents, even Comparative Example 3.1 (0.67%) with a higher crosslinking agent content, required 120 hours for successful peeling; Comparative Examples 3.2 and 3.3, with lower crosslinking agent content, required even longer times. At the same dosage, the longer peeling time required with metal ion crosslinking agents indicates that the gel patches with epoxide crosslinking agents mature significantly faster than those using traditional metal ion crosslinking agents, requiring less epoxide crosslinking agent to achieve the same peeling effect.

[0111] 3.2.2 Examination of Initial Viscosity Test Results The initial tack of each ketoprofen gel patch product was determined during the stability study.

[0112] Test method: Take one sample and place it at 18~25℃ and relative humidity 40%~70% for at least 2 hours. Remove the plastic film and test according to the adhesion test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0952, Method I). The angle of the inclined plate is 45°, and record the residence time of the largest steel ball on the adhesive surface, which should be no less than 5 seconds.

[0113] Table 15 shows some representative examples and comparative test results.

[0114] Table 15 Initial tack test results of the examples and some comparative examples of ketoprofen gel patches

[0115] As can be seen from Examples 3.1 to 3.3, the samples using epoxide crosslinking agents showed little change in initial tack in the stability study and were able to maintain relative stability under both accelerated and long-term conditions; while the comparative examples 3.1 to 3.3 using metal ion crosslinking agents showed a significant decrease in initial tack during the stability test.

[0116] 3.2.3 In vitro release test Ketoprofen gel patches from Examples 3.2 and 3.2 were selected as representatives for in vitro release tests to detect their release after storage under different conditions. The average cumulative release rate is shown in Table 16, and the fluctuation of the average cumulative release rate is shown in Table 17. The units for the average cumulative release rate and the difference between the average cumulative release rates in the tables are %.

[0117] Table 16. Average cumulative release of the gel patch products of Example 3.2 and Comparative Example 3.2

[0118] Preparation of the test solution: Take one ketoprofen gel patch, cut it into a circular slice with a diameter of 15 mm, attach the slice to a semi-permeable membrane, and fix it on a vertical Franz diffusion cell equipped with magnetic stirring. Take samples at 2, 6, 12, and 24 h. The dissolution medium is an acetate medium with a pH of 4.5.

[0119] Preparation of reference solution: Weigh approximately 12 mg of ketoprofen accurately, place it in a 50 mL volumetric flask, dissolve and dilute to the mark with methanol, and shake well; accurately measure 1 mL of the above solution, place it in a 10 mL volumetric flask, dilute to the mark with the medium, and shake well to obtain the reference solution.

[0120] Chromatographic conditions: Column: Kromasil 100-5-C18 150×4.6mm, 5μm; Mobile phase: Acetonitrile-water-glacial acetic acid (45∶55∶0.5); Column temperature: 30℃; Flow rate: 1.0mL / min; Wavelength: 254nm; Injection volume: 10μL; Run time: 10min.

[0121] Table 17 Average cumulative release fluctuation of the gel patch products in Example 3.2 and Comparative Example 3.2

[0122] The release study showed that, under accelerated and long-term conditions, Comparative Example 3.2 showed a significant decrease in the average cumulative release rate in the first 2 hours compared to day 0, with a difference of about 5%, and a difference of 7% to 9% in the first 6 hours. Under accelerated and long-term conditions, the release curve of Example 3.2 remained stable and essentially unchanged over the long term.

[0123] 3.2.4 In vitro transdermal experiment Using pig skin as a barrier, in vitro transdermal tests were conducted using freshly prepared and matured ketoprofen gel patches from Examples 3.2 and 3.3. The results are shown in Table 18. The specific experimental method was as follows: Release conditions: LOGAN SYSTEM 918-12 transdermal diffusion instrument; Release medium: 2.99g sodium acetate dissolved in 1000mL water, 1.6mL glacial acetic acid added, and mixed thoroughly; Test temperature 32℃, rotation speed 600rpm. Skin material was 1-month-old Bama miniature pig skin, 0.6~0.8mm thick, cut into 3×3cm pieces, thawed in physiological saline for about 10 minutes, dried with filter paper, and fixed on the diffusion cell for at least 30 minutes to equilibrate. The gel patch with the cover removed was applied to the skin, and the stirring speed was 600rpm. Sampling time points: 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours.

[0124] Chromatographic conditions: Column: Kromasil 100-5-C18 150×4.6mm, 5μm; Mobile phase: Acetonitrile-water-glacial acetic acid (45∶55∶0.5); Column temperature: 30℃; The average cumulative release rate was determined, and the cumulative permeate percentage (i.e., the cumulative amount of ketoprofen that permeated) was calculated.

[0125] Table 18 Cumulative penetration of ketoprofen in gel patch products of Examples 3.2 and 3.3

[0126] The above results indicate that, in the in vitro transdermal absorption experiment, the drug release rate of each combination of the ketoprofen gel patch products in each embodiment increased at a relatively uniform rate over time.

[0127] The results of the study on the above three gel patch compositions (lidocaine gel patch, loxoprofen sodium gel patch, and ketoprofen gel patch) show that the use of epoxide crosslinking agents can improve the problem of excessively long curing time (>120 hours) of gel patches, and can shorten it to less than 1 / 5 of the time required by metal ion crosslinking agents; the physical properties of the patch products are stable, and after accelerated testing for 6 months (40℃ / 75%RH) and long-term testing for 24 months (25℃ / 60%RH), the adhesion and release curve of the gel patch products remain basically unchanged.

Claims

1. A gel patch composition based on an epoxy crosslinking agent, characterized in that, It includes an epoxide crosslinking agent and a crosslinking backbone material; the epoxide crosslinking agent can form ether bonds with the crosslinking backbone material; the gel patch composition is semi-solid after curing; The epoxide crosslinking agent is a glycerol ether, and the molecule contains two or more epoxy groups; The cross-linked backbone material contains carboxyl groups, including one or two of polyacrylic acid and sodium carboxymethyl cellulose. The epoxide crosslinking agent accounts for 0.01% to 5% of the mass of the gel patch composition; The mass ratio of the epoxide crosslinking agent to the crosslinking backbone material is 1:0.8~1500.

2. The gel patch composition based on an epoxy crosslinking agent according to claim 1, characterized in that, The epoxide crosslinking agent includes one or more of the following: polyglycerol glycidyl ether, polyglycerol polyglycidyl ether, pentaerythritol glycidyl ether, and polyethylene glycol diglycidyl ether.

3. The gel patch composition based on an epoxy crosslinking agent according to claim 1, characterized in that, It also includes a tackifier; the tackifier accounts for less than 40% of the mass of the gel patch composition.

4. The gel patch composition based on an epoxy crosslinking agent according to claim 3, characterized in that, The thickener includes one or more of polyacrylic acid, gelatin, sodium carboxymethyl cellulose, acrylic acid grafted starch, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and polyvinyl alcohol.

5. The gel patch composition based on an epoxy crosslinking agent according to claim 1, characterized in that, It also includes a crosslinking regulator; the crosslinking regulator includes disodium edetate.

6. The gel patch composition based on an epoxy crosslinking agent according to claim 1, characterized in that, The pH value of the gel patch composition is 4-7.

7. The gel patch composition based on an epoxy crosslinking agent according to claim 1, characterized in that, It contains one or two of the active pharmaceutical ingredients of local anesthetics and nonsteroidal anti-inflammatory drugs.

8. The gel patch composition based on an epoxy crosslinking agent according to claim 1, characterized in that, It contains one or more of the active pharmaceutical ingredients, such as lidocaine, loxoprofen sodium, and ketoprofen.

9. The gel patch composition based on an epoxy crosslinking agent according to any one of claims 1 to 8, characterized in that, The epoxide crosslinking agent accounts for 0.02% to 1% of the mass of the gel patch composition; The mass ratio of the epoxide crosslinking agent to the crosslinking backbone material is 1:5~300.

10. The method for preparing the gel patch composition based on an epoxy crosslinking agent as described in any one of claims 1 to 9, characterized in that, First, dissolve and mix the raw and auxiliary materials, except for the epoxide crosslinking agent, and then add the epoxide crosslinking agent and mix well to obtain a gel patch composition.

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