A long-acting sustained-release oral patch based on hot melt extrusion and a preparation method thereof

Abstract

This invention discloses a long-acting sustained-release oral patch based on hot-melt extrusion and its preparation method, belonging to the field of oral care technology. The patch is formed from raw materials containing a film-forming material, a filler, and a cooling substance through a hot-melt extrusion process. The film-forming material is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, and polyvinyl alcohol; the filler includes at least one of microcrystalline cellulose, pregelatinized starch, mannitol, lactose, and carbomer; the patch has a dense, non-porous structure with a porosity ≤1%, and the cumulative release rate of the cooling substance in simulated saliva (pH 6.8, 37℃) is not less than 80% within 120 minutes. This invention achieves a more than 3-fold improvement in long-acting sustained-release effect, reduces production time from over 20 days to several minutes, and shortens the application time to less than 10 seconds. The product completely dissolves without residue and causes no mucosal irritation, solving the problem of existing technologies failing to balance sustained-release effect, production efficiency, and user experience, making it suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of oral care technology, and more specifically, relates to an oral mucosal patch for long-lasting fresh breath and its preparation process. Specifically, it relates to an oral patch prepared by hot melt extrusion process, which can adhere to the oral mucosa for a long time and continuously release freshening ingredients, and is completely dissolved without residue and without mucosal irritation, and its preparation method. Background Technology

[0002] Halitosis is a common problem that affects social confidence. Its root causes lie in an imbalance of the oral microecology, decreased saliva self-cleaning ability, and the production of volatile sulfur compounds by harmful bacteria. Currently, products on the market for instant breath freshening mainly fall into three categories: Chewing gum and lozenges: While they can temporarily mask odor, their effect is short-lived (usually 5-30 minutes), and the chewing or sucking process is unsightly and easily noticed by others. They lack concealment and can interfere with normal speech, drinking, and even eating, potentially causing embarrassment in business settings, dates, and other social situations. Furthermore, to stimulate saliva production, they often contain organic acids such as citric acid, which, with long-term use, can lower the oral pH, erode tooth enamel, and ultimately worsen the oral environment. Mouthwash and spray: They provide immediate and noticeable effects, but the duration is extremely short, making them unsuitable for long-term management, and they are inconvenient to carry. Oral films or patches: Currently, the mainstream preparation method for oral patches is solvent casting (or oral dissolution film process). This method dissolves the film-forming material in water or an organic solvent to form a slurry, which is then coated onto a substrate and cut into patches after a long drying period. However, during the research and development process, the inventors collaborated with several factories capable of producing oral dissolving films and discovered through numerous experiments that the solvent casting method has the following inherent defects, and these defects are interconnected and cannot be overcome by simple adjustments: (1) Extremely low drying efficiency and severely limited thickness: The thickness of the patch is exponentially positively correlated with the drying time. To achieve sustained release, the thickness needs to be increased, but the drying time is drastically extended. Experiments show that when the film thickness increases from 0.6 mm to 2.0 mm, the drying time increases dramatically from several hours to more than 20 days, and the yield is extremely low, making industrial production impossible.

[0003] (2) Limited sustained-release effect with a "ceiling": Even if the thickness is increased to 2.0 mm at the expense of production efficiency, the cooling sensation of the product in simulated saliva lasts for less than 40 minutes, and the cooling sensation is concentrated in the first 15-20 minutes, and then rapidly decays, failing to meet consumers' demand for "long-lasting freshness" (≥2 hours). Repeated experiments show that the solvent casting method inevitably forms a porous structure due to solvent evaporation. This structure rapidly absorbs water and disintegrates upon contact with saliva, leading to the rapid release of active ingredients, which is the "ceiling" of its sustained-release performance.

[0004] (3) Residue exists, resulting in poor user experience: In order to prolong the adhesion time, some solutions use insoluble materials as the skeleton, which results in a thin film remaining after the patch is used and needs to be ejected. It cannot be completely dissolved, which seriously affects the user experience.

[0005] (4) The contradiction between the concentration of cooling substances and mucosal irritation is irreconcilable: if the concentration of cooling substances is increased to enhance the effect, direct contact with the mucosa will cause obvious irritation and discomfort; if the concentration is reduced, the cooling effect will be significantly reduced, failing to meet consumers' expectations for "long-lasting freshness". This is because the single-layer structure of the oral membrane cannot effectively isolate the cooling substances from the mucosa.

[0006] (5) Incompatibility between process and effect: Solvent casting method suffers from a fundamental contradiction: "thickening → exponential increase in drying time → soaring cost" versus "no thickening → insufficient sustained release time". This contradiction has long plagued the field and no effective solution has been found to date. Hot melt extrusion (HME) technology is mostly used in the pharmaceutical field to prepare solid dispersions to improve the solubility of poorly soluble drugs or to prepare immediate-release oral films. Existing published research and patent literature show that the application of hot melt extrusion technology in the field of oral films is concentrated in immediate-release or sustained-release scenarios that rely on insoluble matrix. Those skilled in the art generally have a clear technical bias: films prepared by hot melt extrusion are either only suitable for immediate-release scenarios or must rely on insoluble matrix to achieve long-term sustained release, and cannot prepare long-term sustained-release oral patches that are completely dissolved and leave no residue.

[0007] Those skilled in the art generally believe that fully water-soluble polymer materials, after hot melt extrusion, will rapidly absorb water, swell, and disintegrate upon contact with saliva, making it impossible to achieve a long-lasting sustained release of more than 2 hours. An insoluble matrix is ​​necessary to control the release rate; therefore, no one has ever attempted to prepare long-lasting sustained-release oral patches using fully water-soluble extruders via hot melt extrusion. [1] Elkanayati et al. prepared a sustained-release buccal membrane for the treatment of xerostomia using hot melt extrusion technology. Although the sustained release of the drug was achieved for at least 8 hours, the purpose of their research was the treatment of xerostomia, which is different from the oral freshening application field of the present invention. Moreover, it must rely on the insoluble acrylic resin Eudragit® RSPO as the sustained-release skeleton. The final product cannot be completely dissolved and there is mucosal residue, which does not meet the usage requirements of oral freshening patches that are "dissolved after use and do not need to be removed". [2] Zhang et al. used hydroxypropyl methylcellulose (HPMC) as an auxiliary material to regulate the mucosal adhesion of the oral membrane, but their technical solution still pointed to rapid drug release within 2 hours. They only used HPMC as an adhesion modifier and did not realize that a dense, non-porous continuous skeleton could be formed by the hot melting and plasticizing of HPMC to achieve long-term sustained release. [3] As early as 2003, Repka et al. disclosed the technology of preparing oral drug-loaded films using hot melt extrusion process at 125-130℃, proving that the hot melt extrusion process for preparing oral films has long been a conventional technology in the field. However, for 20 years, those skilled in the art have not been able to break through the above-mentioned technical bias and have failed to develop oral patches that simultaneously meet the requirements of "long-lasting sustained release ≥2 hours, complete dissolution without residue, no mucosal irritation, and industrial continuous production". [4] Brokmann et al. prepared a double-layer drug-loaded oral membrane using hot melt extrusion technology, but it only achieved rapid drug release within 2 hours and used an insoluble backing layer, which also had the defect of not being able to completely dissolve. Existing publicly available patents (such as CN108785285A) all focus on rapid disintegration and immediate release in their hot melt extrusion techniques for preparing oral films, without addressing any designs related to long-lasting sustained release. This prior art clearly demonstrates that those skilled in the art generally limit hot melt extrusion technology to the preparation of "immediate-release oral films" or "insoluble matrix sustained-release films," failing to recognize that the anhydrous melt plasticization characteristics of hot melt extrusion can be used to prepare dense, non-porous, fully water-soluble oral patches to achieve long-lasting sustained release of over 2 hours. Furthermore, existing technologies cannot simultaneously meet the comprehensive performance requirements of oral freshening patches, and there are no reports of successful applications of related technical solutions. Summary of the Invention (a) Technical problems to be solved The purpose of this invention is to overcome the shortcomings of existing technologies, especially the five major defects of solvent casting methods: "extremely low drying efficiency, poor sustained-release effect, insoluble residues, irritation of the mucosa by cooling substances, and inability to balance process and effect." At the same time, it overcomes the technical prejudice in the field that "hot melt extrusion is only suitable for immediate-release oral films and must rely on insoluble matrix to achieve long-term sustained release." This invention provides a long-term sustained-release oral patch prepared based on hot melt extrusion process, which can be continuously adhered to the oral mucosa for more than 2 hours and achieve a lasting and uniform release of cooling sensation and aroma. It also has excellent properties such as complete solubility, no irritation, and continuous industrial production. To achieve the above objectives, the present invention adopts the following technical solution: A long-acting sustained-release oral patch based on hot melt extrusion is made by melt extrusion molding of raw materials containing film-forming materials, fillers and cooling substances through a hot melt extrusion process; The film-forming material includes at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, and polyvinyl alcohol; The filler includes at least one of microcrystalline cellulose, carbomer, pregelatinized starch, mannitol, and lactose; The patch has a dense, non-porous structure with a porosity of ≤1%; The cooling substance exhibits a cumulative release rate of no less than 80% within 120 minutes in simulated saliva (pH 6.8, 37°C). Furthermore, the patch also contains a sweetener and a flavoring.

[0008] In this invention, "sweetening substances" refer to compounds that produce a sweet taste by stimulating sweet taste receptors in the oral cavity, including but not limited to sugar alcohols (xylitol, sorbitol, maltitol, erythritol), high-intensity sweeteners (steviosides, mogrosides, allulose, tagatose), etc. These substances are widely recognized as sweeteners or sweetening substances in the food and oral care fields. Regardless of whether they also have other functions (such as filling or moisturizing), as long as their function is to provide a sweet taste, they fall within the scope of sweetening substances described in this invention.

[0009] In this invention, "cooling substances" refer to compounds that produce a cooling sensation by stimulating oral cold receptors (such as TRPM8 receptors), including but not limited to menthol, menthyl lactate, WS-3, WS-23, WS-12, and isoprene. These substances are widely recognized as cooling agents or cooling substances in the food and oral care fields. Regardless of whether they simultaneously possess other properties (such as fragrance), as long as their function is to provide a cooling sensation, they fall within the scope of cooling substances described in this invention.

[0010] In this invention, "film-forming material" refers to a substance capable of forming a continuous film skeleton during hot melt extrusion, including but not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol, etc. Those skilled in the art will understand that other polymeric materials with similar thermoplasticity, film-forming properties, and biocompatibility, as long as they can achieve the long-term sustained-release objective of this invention, also fall within the scope of film-forming materials described in this invention.

[0011] In this invention, "filler" refers to substances that can adjust the mechanical strength of patches, improve extrusion molding performance, and enhance adhesiveness, including but not limited to microcrystalline cellulose, carbomer, pregelatinized starch, mannitol, and lactose. Those skilled in the art will understand that other pharmaceutical or food-grade fillers with similar functions also fall within the scope of fillers described in this invention.

[0012] Furthermore, the oral patch has a multi-layered structure, comprising at least: Outer layer: Contains no cooling substances, consists of film-forming materials and fillers, and is used to contact the oral mucosa and provide initial adhesion; Inner layer: Contains cooling substances and is composed of film-forming materials, fillers, and cooling substances to slowly release cooling ingredients; The outer and inner layers are co-extruded together by hot melt extrusion to form an integral structure. Further, the oral patch is prepared through the following steps: (1) Mix the raw materials evenly according to the proportion to obtain a dry powder mixture; (2) The dry powder mixture is fed into a hot melt extruder and melt extruded at a temperature of 120-180℃ and a screw speed of 50-200rpm to obtain a continuous sheet or strip extrudate; (3) Cool and solidify the extrudate, and cut it to obtain an oral patch. Preferably, the hot melt extruder in step (2) is a twin-screw extruder with a screw length-to-diameter ratio of 25:1 to 40:1, and is equipped with a flat extrusion die with a die thickness of 1.5-3.0 mm. Compared with existing technologies, the present invention achieves the following unexpected technical effects, which cannot be achieved by existing solvent casting methods or existing hot melt extrusion oral film agents: Revolutionary improvement in production efficiency and cost: Solvent casting method requires drying for more than 20 days to prepare a 2mm thick film. The drying energy consumption is extremely high and the equipment occupation cycle is extremely long, resulting in a surge in production costs and an extremely low yield, making it impossible to achieve industrial production. This invention adopts continuous hot melt extrusion production, with a single batch production time of only a few minutes. The production efficiency has achieved a leap from "days" to "minutes". The drying energy consumption is almost zero and the production cost is greatly reduced. It completely solves the industry problem of being unable to balance "slow-release effect" with "production efficiency and production cost". The leap in sustained-release performance overcomes the long-standing technical bias in the field: at the same or similar thickness, the cumulative release rate of the cooling substance in the product of this invention is ≥80% after 120 minutes, corresponding to a long-lasting refreshing time of more than 120 minutes. In contrast, even if the thickness of the solvent casting method is increased to 2 mm at the expense of production efficiency, its sustained-release time is still less than 40 minutes, achieving an improvement of more than 3 times. At the same time, compared with the existing technology [1] which must rely on an insoluble skeleton to achieve long-lasting sustained release, this invention uses fully water-soluble food-grade excipients, which completely dissolve without residue while achieving long-lasting sustained release. This breaks the common perception in the field that "hot melt extrusion either has rapid release or must use an insoluble skeleton to achieve sustained release," and overcomes the technical bias that has lasted for 20 years. This technical effect of taking into account both long-lasting sustained release and complete dissolution exceeds the reasonable expectations of those skilled in the art and cannot be obtained through conventional experiments. Complete dissolution, no residue: The product of this invention completely dissolves after the cooling substance is fully released, leaving no residue. Comparative Examples 1 and 2 used the exact same formulation as this invention, but were prepared using solvent casting, and their sustained-release time was still less than 40 minutes, proving that the performance leap stems from process innovation. However, in pursuit of long-lasting adhesion, commercially available solvent casting products generally require the addition of an insoluble polymer backbone. Existing technologies [1,4] also use an insoluble backing layer / backbone, which directly leads to the need to eject residual film after use, seriously affecting the user experience. This invention, through a dense structure formed by hot melt extrusion, achieves long-lasting sustained release while ensuring complete dissolution, completely solving the residue problem. A breakthrough in eliminating mucosal irritation: This invention can be designed as a double-layer structure. The outer layer contains no cooling substance and directly contacts the mucosa, providing gentle initial adhesion; the inner layer contains the cooling substance, which is slowly released through the dissolution of the film-forming material. This structure avoids direct contact between the cooling substance and the mucosa, completely resolving the contradiction of "high concentration causing irritation, low concentration causing ineffectiveness" in single-layer structures. Experiments have shown that the comfort score of the double-layer structure patch (9.2 / 10) is significantly higher than that of the single-layer structure (6.5 / 10), and no stinging sensations were reported. In contrast, the orally dissolving film process cannot achieve multi-layer co-extrusion, thus failing to avoid direct contact between the cooling substance and the mucosa. Specialized division of functions: The multilayer structure of this invention enables functional zoning—the outer layer is dedicated to adhesion, and a higher proportion of film-forming materials can be used to enhance initial adhesion; the inner layer is dedicated to sustained release, and a higher proportion of fillers can be used to adjust the release rate. This "functional zoning" allows for more flexible material selection for each layer, resulting in overall performance superior to a single-layer structure. The fundamental structural innovation lies in the fact that solvent casting inevitably creates a porous structure due to solvent evaporation, which is the root cause of its rapid disintegration, insufficient sustained release, and unavoidable residues. In contrast, the hot-melt extrusion process used in this invention involves anhydrous melt plasticization, resulting in a dense, non-porous solid dispersion. This is the structural basis for achieving long-lasting sustained release, complete dissolution, and non-irritating properties. This structural difference stems from the fundamental difference in processes and cannot be achieved by simply adjusting solvent casting parameters. Scanning electron microscopy (SEM) observation shows that the cross-section of the product from this invention has no visible pores, with a porosity ≤1%; while the cross-section of the solvent casting product of the same thickness exhibits a distinct porous network structure with a porosity ≥15%. This structural difference is precisely what leads to the essential difference in their sustained-release performance. Optimized taste and experience: Natural sweetness is provided by sweeteners such as xylitol, steviol glycosides, and mogrosides, combined with the cooling sensation of menthol and the instant sour stimulation of malic acid / citric acid, achieving a layered taste sensation of "slightly sour on the first sip, followed by coolness, and a lingering sweet aftertaste." It is also sugar-free and will not cause tooth decay. Furthermore, this invention uses a patch form, making it completely invisible during use and not interfering with normal speech, drinking, or even eating. It completely avoids the social embarrassment of chewing gum or lozenges, further enhancing the user experience. Stable process and suitable for large-scale production: Hot melt extrusion is a continuous production process with good batch reproducibility. The resulting patches have uniform thickness, high mechanical strength, and are easy to cut and package, meeting the requirements of industrial production. Safe ingredients and no health risks: All raw materials are food-grade or pharmaceutical-grade, contain no organic solvent residues, and do not contain harmful preservatives, making them safe for long-term use. Detailed Implementation

[0013] The present invention will be further illustrated below through specific embodiments and comparative examples. The inventors established the technical solution of this invention only after numerous experiments (including but not limited to repeated attempts and failures in the compressed candy process and solvent casting process). The following embodiments fully demonstrate the advancement and inventiveness of this invention. The raw materials are weighed according to the following percentages by weight: xylitol 47.09%, hydroxypropyl methylcellulose (HPMC) 28.00%, microcrystalline cellulose (MCC) 4.50%, xanthan gum 1.10%, green tea flavor 6.00%, menthol 1.80%, green tea extract 0.01%, malic acid 2.50%, citric acid 2.00%, steviol glycosides 6.00%, and mogrosides 1.00%.

[0014] All raw materials were mixed in a high-speed mixer for 5 minutes to obtain a homogeneous dry powder mixture. The mixture was then fed into a twin-screw hot melt extruder, with the extrusion temperature zones set as follows: Zone 1 140°C, Zone 2 150°C, Zone 3 160°C, and Die Zone 155°C; screw speed 120 rpm. The extrudate was continuously extruded in a strip from a flat die (die thickness 2.2 mm) and immediately cooled and solidified by a 10°C cooling roller to obtain a film approximately 2.2 mm thick. The film was cut into 12 mm diameter circular patches and packaged in aluminum foil. The formulation is the same as in Example 1, but the extrusion temperature is adjusted as follows: 135°C in the first zone, 145°C in the second zone, 155°C in the third zone, and 150°C in the die zone; the screw speed is 100 rpm. The remaining steps are the same as in Example 1, resulting in a patch with a thickness of approximately 2.2 mm. In Example 1, hydroxypropyl methylcellulose was replaced with hydroxypropyl cellulose (HPC), and the rest of the formulation and process were the same as in Example 1, resulting in a patch with a thickness of approximately 2.2 mm. Using the formulation and process of Example 1, patches with thicknesses of 1.5 mm, 2.0 mm, 2.5 mm, and 3.0 mm were prepared by adjusting the thickness of the extrusion die, and their sustained-release performance and comfort were tested. The results showed that when the thickness was less than 1.5 mm, the sustained-release time was difficult to reach 120 minutes (which does not meet the core requirements of this invention); when the thickness was greater than 3.0 mm, the wearing comfort decreased, and it may affect normal speaking and drinking, reducing practicality.

[0015] Therefore, the thickness is preferably controlled within the range of 1.5-3.0 mm, and more preferably 2.0-2.5 mm. The outer layer is composed of the following raw materials by weight percentage: 65.0% hydroxypropyl methylcellulose (HPMC), 20.0% microcrystalline cellulose (MCC), and 15.0% xylitol. All raw materials are mixed evenly to form the outer layer material.

[0016] The inner layer is composed of the following raw materials by weight percentage: xylitol 47.09%, hydroxypropyl methylcellulose (HPMC) 28.00%, microcrystalline cellulose (MCC) 4.50%, xanthan gum 1.10%, green tea flavoring 6.00%, menthol 1.80%, green tea extract 0.01%, malic acid 2.50%, citric acid 2.00%, steviol glycosides 6.00%, and mogrosides 1.00%. All raw materials are mixed thoroughly to form the inner layer.

[0017] Preparation method: The outer and inner layer raw materials are fed into two independent feeders of a twin-screw hot melt extruder, and extruded in one pass through a co-extrusion die, with the outer layer wrapping the inner layer. The extrusion temperature is 150~160℃, and the screw speed is 120 rpm. The extrudate is continuously extruded in a strip from a flat die (die thickness 2.5 mm) and immediately cooled and solidified by a 10℃ cooling roller to obtain a composite film with an outer layer thickness of approximately 0.3 mm and an inner layer thickness of approximately 2.2 mm. The film is cut into circular patches with a diameter of 12 mm and packaged in aluminum foil. The raw materials are weighed according to the following percentages by weight: xylitol 47.09%, hydroxypropyl methylcellulose (HPMC) 28.00%, carbomer 974P 4.50%, xanthan gum 1.10%, green tea flavor 6.00%, menthol 1.80%, green tea extract 0.01%, malic acid 2.50%, citric acid 2.00%, steviol glycosides 6.00%, and mogrosides 1.00%.

[0018] All raw materials were mixed in a high-speed mixer for 5 minutes to obtain a homogeneous dry powder mixture. The mixture was then fed into a twin-screw hot melt extruder, with the extrusion temperature zones set as follows: Zone 1 140°C, Zone 2 150°C, Zone 3 160°C, and Die Zone 155°C; screw speed 120 rpm. The extrudate was continuously extruded in a strip from a flat die (die thickness 2.2 mm) and immediately cooled and solidified by a 10°C cooling roller to obtain a film approximately 2.2 mm thick. The film was cut into 12 mm diameter circular patches and packaged in aluminum foil. Using the same formula as in Example 1, water-soluble components such as HPMC and xanthan gum were dissolved in purified water, and xylitol, sweeteners, flavorings, menthol, etc. were added. The mixture was stirred evenly, coated onto a glass plate, and dried at 50°C (0.5 mm thickness) for about 4 hours. After peeling off the film, the film was cut into patches of the same size. Using the same formulation as in Example 1 and prepared according to the method of Comparative Example 1, but by increasing the coating amount, the dried thickness was increased to 2.0 mm. Due to the increased thickness, the drying time was extended to more than 20 days, and the film exhibited cracking and unevenness, resulting in an extremely low yield. Although samples suitable for laboratory testing were obtained by drastically extending the drying time, the films suffered from severe internal stress cracks and uneven thickness, with a yield of less than 30%, making industrial-scale production completely impractical. Experimental Examples and Effect Verification

[0019] All experiments were repeated three times. Data are expressed as mean ± standard deviation. Statistical analysis was performed using SPSS software. p < 0.05 was considered statistically significant. The patches of Examples 1-6 and Comparative Examples 1-2 were placed in simulated saliva (pH 6.8, prepared according to the artificial saliva formula in the 2025 edition of the Pharmacopoeia of the People's Republic of China) at a constant temperature of 37°C and continuously stirred. Samples were taken at 15 min, 30 min, 60 min, 90 min and 120 min respectively, and the cumulative release of menthol was detected by high performance liquid chromatography (HPLC). The results are shown in Table 1.

[0020] Table 1. Results of Cumulative Release of Cooling Substances in Each Experimental Group sample thickness 30-minute cumulative release 60-minute cumulative release Cumulative release rate over 120 minutes Example 1 2.2 mm 22.4% 48.7% 92.3% Example 2 2.2 mm 24.1% 51.2% 90.7% Example 3 2.2 mm 21.8% 47.5% 91.5% Example 4 (1.5mm) 1.5 mm 28.6% 56.3% 88.2% Example 4 (2.5mm) 2.5 mm 19.2% 42.6% 93.5% Example 5 2.5 mm 17.5% 39.8% 88.7% Example 6 2.2 mm 23.0% 49.2% 91.8% Comparative Example 1 0.5 mm 98.6% 100% 100% Comparative Example 2 2.0 mm 82.3% 96.7% 100% The results showed that the cooling substance in all embodiments of the present invention had a cumulative release rate of ≥88% within 120 minutes, which met the core requirement of ≥80% in claim 1, and achieved a uniform and long-lasting release effect. In contrast, Comparative Example 1 was almost completely released within 30 minutes, and Comparative Example 2 was basically completely released within 60 minutes, which could not achieve long-lasting sustained release, fully demonstrating the sustained release performance advantage of the present invention. The patches from Examples 1-6 and Comparative Examples 1-2 were placed in simulated saliva (pH 6.8, prepared according to the artificial saliva formula in the 2025 edition of the Pharmacopoeia of the People's Republic of China) at a constant temperature of 37°C with continuous stirring. Ten trained sensory evaluators recorded the intensity of the cooling sensation (1-5 points) every 15 minutes. The effective duration was defined as the time point with an average score ≥1.5 points (out of 5). The results are shown in Table 2.

[0021] Table 2. Results of in vitro sustained-release sensory tests for each experimental group sample thickness structure Drying time Duration of cooling sensation Are there any residues after application? Example 1 2.2 mm single layer Not applicable (continuous extrusion) >120 minutes Completely dissolved, with no residue. Example 2 2.2 mm single layer Not applicable (continuous extrusion) >120 minutes Completely dissolved, with no residue. Example 3 2.2 mm single layer Not applicable (continuous extrusion) >120 minutes Completely dissolved, with no residue. Example 4 (1.5mm) 1.5 mm single layer Not applicable (continuous extrusion) >120 minutes Completely dissolved, with no residue. Example 4 (2.5mm) 2.5 mm single layer Not applicable (continuous extrusion) >150 minutes Completely dissolved, with no residue. Example 5 2.5 mm Double layer Not applicable (continuous extrusion) >150 minutes Completely dissolved, with no residue. Example 6 2.2 mm single layer Not applicable (continuous extrusion) >120 minutes Completely dissolved, with no residue. Comparative Example 1 0.5 mm single layer 4 hours <15 minutes Completely dissolved Comparative Example 2 2.0 mm single layer >20 days <40 minutes Complete dissolution can lead to membrane cracking. The results showed that the cooling sensation of the embodiments of the present invention could last for 120-150 minutes, and some embodiments could last for more than 150 minutes, while Comparative Example 1 (0.5 mm) lasted for less than 15 minutes, and Comparative Example 2 (2.0 mm) lasted for less than 40 minutes. The present invention achieved more than 3 times the improvement in sustained release time at similar thickness, and shortened the production time from more than 20 days to a few minutes, with the product completely dissolved and leaving no residue. The patch was placed on fresh, isolated porcine oral mucosa tissue. The time from contact to the point where a perceptible resistance was generated between the patch and the mucosa (defined as the patch not slipping when gently pulled with tweezers) was recorded. Simultaneously, a texture analyzer was used to test the adhesion of the patch after 10 seconds of contact. Each test was repeated three times. The results are as follows: (1) Examples 1-6 (the present invention): all can produce strong adhesion within 10 seconds, and the adhesion force is ≥0.12N / cm at 10 seconds, which meets the requirement of ≥0.1N / cm; (2) Comparative Examples 1-2 (solvent casting method): Both require 5-10 minutes to gradually soften and adhere, and have no effective adhesion after 10 seconds. The results show that the present invention reduces the application time from several minutes to several seconds, achieving an order-of-magnitude improvement, which fully demonstrates that the present invention achieves an instant application user experience, while the prior art requires a long waiting time, and the user experience is significantly inferior to that of the present invention. The patches of Example 1 (single layer), Example 5 (double layer), Example 6 (carbomer formulation), and Comparative Example 2 were applied to the oral mucosa of 20 volunteers and removed after 2 hours. Discomfort was recorded, and the results are shown in Table 3.

[0022] Table 3. Results of mucosal irritation test for each experimental group sample Number of people reporting stinging sensation Comfort rating (1-10 points) Comparative Example 2 6 people (30%) 6.2 Example 1 (Single Layer) 1 person (5%) 6.5 Example 5 (Double Layer) 0 people (0%) 9.2 Example 6 (Carbomer Formulation) 0 people (0%) 9.0 The results showed that 30% of volunteers in Comparative Example 2 reported a stinging sensation; although Example 1 (single layer) showed significant improvement, one person still reported mild discomfort; while Example 5 (double layer structure) and Example 6 (carbomer formula) had no reported discomfort and the highest comfort scores. This fully demonstrates that both the double layer structure and the carbomer formula can effectively solve the problem of cooling substances irritating the mucous membrane. The patch was applied to fresh isolated porcine oral mucosa and placed in a humid environment at 37°C. The time for the patch to detach was recorded. At the same time, the difference between the time when the cumulative release of the cooling substance reached 80% and the average adhesion time of the patch was compared with the release data from Experiment 1. The results are shown in Table 4.

[0023] Table 4. Results of Adhesion Force and Release Synchronization Tests for Each Experimental Group sample Average adhesion time Time to reach 80% release absolute value of the time difference between the two Example 1 (Single Layer) 3.5 hours 102 minutes 8 minutes Example 5 (Double Layer) 4.0 hours 115 minutes 5 minutes Example 6 (Carbomer Formulation) 3.8 hours 108 minutes 12 minutes Comparative Example 1 1.2 hours 12 minutes 60 minutes Comparative Example 2 1.8 hours 28 minutes 80 minutes The 20 volunteers who participated in the taste evaluation unanimously reported that after the cooling sensation disappeared, the patch usually dissolved completely without needing to be removed, providing a natural experience. This contrasts sharply with the solvent casting method (comparative example), which requires spitting out residual film after use, further demonstrating the significant advantages of this invention in terms of user experience. The patch samples from Examples 1, 6 and Comparative Example 2 were sputter-coated with gold and their cross-sectional morphology was observed using a scanning electron microscope. The accelerating voltage was 10 kV and the magnification was 1000x.

[0024] The results showed that the patch cross-sections of Examples 1 and 6 were dense and uniform with no visible pores, and the porosity was calculated to be ≤1% based on image analysis. The patch cross-section of Comparative Example 2 exhibited a distinct porous mesh structure with widely distributed pores, and the porosity was calculated to be ≥15% based on image analysis. These results directly demonstrate the fundamental structural difference between this invention and existing solvent casting products. It is precisely this dense, non-porous structure that achieves the core effect of long-lasting sustained release. References

[0025] [1] Elkanayati RM, Darwesh AY, Taha I, et al. Quality by design approach for fabrication of extended-release buccal films for xerostomia employing hot-melt extrusion technology[J]. European Journal of Pharmaceuticsand Biopharmaceutics, 2024, 200: 114335. [2] Zhang Z, Feng S, El-Kanayati R, et al. Novel development of Poly(2-ethyl-2-oxazoline)-based mucoadhesive buccal film for poorly water-soluble drug delivery via hot-melt extrusion[J]. European Journal of Pharmaceuticsand Biopharmaceutics, 2025, 210: 114686. [3] Repka M A, et al. Production and characterization of hot-meltextruded films containing clotrimazole[J]. Drug Development and IndustrialPharmacy, 2003, 29(9): 1043-1051. [4] Brokmann F, Luthe K, Hartmann J, et al. Hot Melt Extrusion asContinuous Manufacturing Technique to Produce Bilayer Films Loaded withParacetamol or Lactase[J]. Pharmaceuticals, 2025, 18(3): 310。

Claims

1. A long-acting sustained-release oral patch based on hot melt extrusion, characterized in that, The patch is made by melt extrusion molding of raw materials containing film-forming materials, fillers, and cooling substances through a hot melt extrusion process; the film-forming material is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, and polyvinyl alcohol; the filler is selected from at least one of microcrystalline cellulose, pregelatinized starch, mannitol, lactose, and carbomer; the patch has a dense, non-porous structure with a porosity of ≤1%, and the cumulative release rate of the cooling substance in simulated saliva (pH 6.8, 37°C) is not less than 80% within 120 minutes.

2. The oral patch according to claim 1, characterized in that, The raw materials also include sweeteners and flavorings.

3. The oral patch according to claim 2, characterized in that, The sweetener is selected from at least one of xylitol, sorbitol, maltitol, erythritol, steviol glycosides, mogrosides, allulose, and tagatose.

4. The oral patch according to claim 2, characterized in that, The raw materials also include an acidulant, which is selected from at least one of malic acid, citric acid, and tartaric acid.

5. The oral patch according to claim 1, characterized in that, The film-forming material is hydroxypropyl methylcellulose.

6. The oral patch according to claim 1, characterized in that, The filler is microcrystalline cellulose or carbomer.

7. The oral patch according to claim 1, characterized in that, The patch is an integral multilayer structure formed by hot melt extrusion co-extrusion, comprising at least: (1) an outer layer: without cooling substances, composed of film-forming materials and fillers, for contacting the oral mucosa and providing initial adhesion; (2) an inner layer: containing cooling substances, composed of film-forming materials, fillers and cooling substances, for slowly releasing cooling components.

8. The oral patch according to claim 7, characterized in that, The outer layer has a thickness of 0.2-0.5 mm, and the inner layer has a thickness of 1.0-2.5 mm.

9. The oral patch according to claim 7, characterized in that, The outer layer contains a higher proportion of film-forming material by mass than the inner layer; the inner layer contains a higher proportion of filler by mass than the outer layer.

10. The oral patch according to any one of claims 1-9, characterized in that, The thickness of the patch is 1.5-3.0 mm.

11. The oral patch according to claim 10, characterized in that, The thickness of the patch is 2.0-2.5 mm.

12. The oral patch according to any one of claims 1-11, characterized in that, The patch generates an adhesive force of not less than 0.1 N / cm within 10 seconds of contacting the oral mucosa.

13. The oral patch according to any one of claims 7-11, characterized in that, The absolute value of the difference between the time required for the cumulative release of the cooling substance in simulated saliva (pH 6.8, 37°C) to reach 80% and the average adhesion duration of the patch on the oral mucosa is no more than 15 minutes.

14. A method for preparing an oral patch as described in any one of claims 1-13, characterized in that, The process includes the following steps: (1) mixing the raw materials evenly to obtain a dry powder mixture; (2) putting the dry powder mixture into a hot melt extruder and performing melt extrusion at a temperature of 120-180℃ and a screw speed of 50-200 rpm to obtain a continuous sheet or strip extrusion; (3) cooling and solidifying the extrusion and cutting it to obtain an oral patch.

15. A method for preparing an oral patch as described in any one of claims 7-13, characterized in that, The process includes the following steps: (1) Mixing the raw materials for forming the outer and inner layers evenly to obtain the corresponding dry powder mixtures; (2) Feeding each layer of dry powder mixture into different independent feed ports of a hot melt extruder, and extruding it through a co-extrusion die at a temperature of 120-180℃ and a screw speed of 50-200 rpm to obtain a continuous strip-shaped composite extrusion; (3) Cooling and solidifying the extrusion, and cutting it to obtain an oral patch.

16. The preparation method according to claim 14 or 15, characterized in that, The hot melt extruder is a twin-screw extruder with a screw length-to-diameter ratio of 25:1 to 40:1, and is equipped with a flat extrusion die with a die thickness of 1.5-3.0 mm.

17. The preparation method according to claim 14 or 15, characterized in that, The extrusion temperature in step (2) is 150~160℃.