A long-acting sustained-release sleep aid nasal inhaler combining microcapsule technology and hydrogel technology and its preparation method.

Abstract

This invention belongs to the field of personal health care and functional materials, and specifically relates to a long-acting sustained-release nasal inhaler combining microcapsule technology and hydrogel technology, and its preparation method. A method for preparing a long-acting sustained-release nasal inhaler combining microcapsule technology and hydrogel technology includes the following steps: S1, preparing compound essential oil microcapsule powder; S2, preparing a hydrogel matrix; S3, mixing the compound essential oil microcapsule powder and the hydrogel matrix at a mixing speed of 100-200 rpm for 15-30 min to obtain the nasal inhaler. The preparation method of this invention, by constructing a dual sustained-release system of "microcapsule-hydrogel," significantly prolongs the action time of the active ingredients, aiming for a sustained-release duration exceeding 24 hours, and making its release curve more stable, avoiding the problems of initial overconcentration and later inactivation, thus achieving long-acting, stable, and controllable release of essential oils.

Description

Technical Field

[0001] This invention belongs to the field of personal health care and functional materials, and specifically relates to a long-acting sustained-release sleep aid nasal inhaler combining microcapsule technology and hydrogel technology and its preparation method. Background Technology

[0002] Currently, aromatherapy-based sleep aids are increasingly appearing on the market, mainly in the form of diffusers, scented candles, solid perfumes, and nasal inhalers. These products work by having users inhale the volatile essential oil components, which act on the olfactory nervous system, thereby regulating mood and sleep. However, existing technologies still have significant limitations in terms of product form, duration of efficacy, and user experience, as detailed below: 1. Traditional essential oil direct-use products: Most nasal inhalers or aromatherapy devices on the market today use a method of directly adsorbing liquid essential oils into porous carrier materials (such as cotton wicks, diatomaceous earth, volcanic rock, etc.).

[0003] The significant drawback of this technical solution lies in the uncontrollable release process of the essential oils. Initially, the rapid evaporation results in a strong, pungent odor, which quickly diminishes and becomes ineffective later, leading to a short effective duration (typically only 1-4 hours). This "burst" release not only fails to provide a stable and lasting sleep-inducing stimulus but may also cause discomfort due to the excessively high initial concentration. Furthermore, liquid essential oils are easily oxidized when directly exposed to air, leading to degradation of active ingredients and deterioration of aroma, resulting in poor product stability.

[0004] 2. Attempts to improve single sustained-release technologies: To improve release behavior, some studies have introduced sustained-release technologies. For example: 1) Microencapsulation technology: Essential oils are encapsulated into microcapsules using wall materials such as β-cyclodextrin and gelatin, which delays volatilization to some extent. However, when microcapsule powder is simply encapsulated in a breathable bag or coated onto a carrier, its release rate is still greatly affected by the ambient temperature and humidity, and there is a lack of further means to regulate the release kinetics, making it difficult to achieve a truly long-lasting sustained release of more than 12 hours.

[0005] 2) Gel carrier technology: Some studies have also used gels such as carbomer and agarose as carriers for essential oils. However, traditional gels often lack intelligent responsiveness, have limited capacity and protection for essential oils, and their physical form (mostly solid or semi-solid) is not suitable for making portable nasal inhalers, or may cause stickiness and drying issues for the user experience.

[0006] In summary, current technologies have not yet adequately addressed the core challenge of balancing long-lasting, stable release with a superior user experience in sleep-aid nasal inhalers. Specifically, there is a lack of a technological solution capable of efficiently encapsulating and protecting essential oils, and releasing them on demand (e.g., triggered by nasal temperature) and in a stable manner for over 24 hours or even longer. Summary of the Invention

[0007] The purpose of this invention is to provide a long-acting sustained-release sleep aid nasal inhaler that combines microcapsule technology and hydrogel technology, and its preparation method.

[0008] A method for preparing a long-acting sustained-release nasal inhaler combining microcapsule technology and hydrogel technology includes the following steps: S1. Preparation of compound essential oil microcapsule powder; S2. Preparation of hydrogel matrix; S3, by weight percentage, the compound essential oil microcapsule powder is 5-15%, and the hydrogel matrix is ​​85-95%; The compound essential oil microcapsule powder was mixed with the hydrogel matrix under ice bath conditions of 4-8℃, with a mixing speed of 100-200 rpm and a time of 15-30 min to obtain a nasal inhaler.

[0009] Furthermore, in step S1, the specific method for preparing the compound essential oil microcapsule powder is as follows: S11. Preparation of wall material solution: Accurately weigh β-cyclodextrin, add it to deionized water and dissolve it to obtain the wall material solution; S12. Preparation of essential oil core material: Linaloyl acetate, linalool, limonene, patchouli alcohol, sandalwood alcohol, citronellol, and ashwagandha essential oil are mixed and dissolved in anhydrous ethanol to form a clear essential oil ethanol solution, thus obtaining the essential oil core material. S13. The essential oil core material is added to the wall material solution to carry out an inclusion reaction, resulting in a reaction solution.

[0010] S14. The reaction solution is subjected to standing, precipitation, washing, centrifugation, purification, drying and grinding in sequence to obtain compound essential oil microcapsule powder.

[0011] Furthermore, in step S11, the concentration of β-cyclodextrin is 177.8 g / L.

[0012] Further, in step S12, the following components are present in mass percentile: 20%-30% linaloyl acetate, 15%-25% linalool, 5%-10% limonene, 3%-5% patchouli alcohol, 3%-5% sandalwood alcohol, 1%-3% citronellol, and 35%-40% ashwagandha essential oil.

[0013] Furthermore, in step S13, the mixing ratio of the essential oil core material to the wall material solution is 1:15.

[0014] Furthermore, in step S2, the specific steps for preparing the hydrogel matrix are as follows: S21. Accurately weigh the chitosan powder and slowly add it to a 2% (w / w) glacial acetic acid solution. Stir magnetically until completely dissolved to obtain a transparent and viscous chitosan solution. S22. Weigh out sodium β-glycerophosphate, dissolve it in phosphate buffer, filter to remove bacteria, and obtain a cross-linking agent solution; S23. Cool the chitosan solution in an ice bath while stirring, and add the crosslinking agent solution at a dropping rate of 1 mL / min. After the addition is complete, continue stirring in the ice bath for 30 min to obtain the hydrogel matrix.

[0015] Furthermore, in step S21, the concentration of the chitosan solution is 2%; In step S22, the concentration of sodium β-glycerophosphate is 56% (w / v); In step S23, the volume ratio of chitosan solution to crosslinking agent solution is 3:1.

[0016] The above preparation method yields a long-acting, sustained-release nasal inhaler for sleep aid.

[0017] The application of the above-mentioned long-acting sustained-release sleep aid nasal inhaler in the preparation of nasal inhalation products.

[0018] Compared with the prior art, the present invention has significant advantages and beneficial effects, specifically reflected in the following aspects: (1) The preparation method described in this invention significantly prolongs the action time of the active ingredients by constructing a dual sustained-release system of "microcapsule-hydrogel". The target sustained-release time exceeds 24 hours, and the release curve is more stable, avoiding the problems of excessive concentration in the early stage and failure in the later stage, so as to achieve long-term, stable and controllable release of essential oils.

[0019] (2) The preparation method described in this invention uses microencapsulation technology to encapsulate the active ingredients of essential oils in a wall material (such as β-cyclodextrin), thereby isolating them from the external environment (light, oxygen, and moisture), thus protecting the core ingredients from a physicochemical perspective, delaying degradation, maintaining efficacy, and significantly improving the stability of essential oils and the shelf life of the product.

[0020] (3) The preparation method described in this invention reduces the initial concentration of essential oil upon nasal contact through a sustained-release mechanism, thereby reducing irritation. Simultaneously, it utilizes a biocompatible thermosensitive hydrogel as the substrate to ensure safety upon contact with the human body, and leverages its thermosensitive properties to optimize release, improving safety and comfort during use.

[0021] (4) The preparation method described in this invention utilizes the properties of thermosensitive hydrogels to keep the product stable at room temperature, while when it approaches or comes into contact with the temperature of the human nasal cavity (about 30-34°C), its gel network structure undergoes reversible changes, thereby "triggering" and regulating the release rate of essential oils in microcapsules, achieving intelligent release that is closer to physiological needs, and providing an intelligent responsive release mechanism.

[0022] (5) The preparation method of the present invention uniformly disperses the protected microcapsules in a flowable / semi-flowable hydrogel precursor solution and finally encapsulates them in a portable nasal inhalation container to form an integrated product form that is ready to use, accurate in dosage, hygienic and clean, creating an integrated and easy-to-use product form. Attached Figure Description

[0023] Figure 1 The graph shows the in vitro release rate test results of the nasal inhaler prepared in Example 1 of this invention. Detailed Implementation

[0024] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings. Furthermore, unless otherwise specified, the above embodiments and features described herein can be combined with each other.

[0025] The primary objective of this invention is to protect a method for preparing a long-acting, sustained-release nasal inhaler that combines microencapsulation and hydrogel technologies, comprising the following steps: (1) Preparation of compound essential oil microcapsule powder, specifically including the following steps: S1. Preparation of wall material solution: Accurately weigh β-cyclodextrin, add it to deionized water, heat to 120°C and stir at high speed until completely dissolved to form a homogeneous and transparent solution. Then cool to 80°C for later use to obtain the wall material solution. The concentration of β-cyclodextrin is 177.8 g / L. S2. Preparation of essential oil core materials: Weigh the following essential oil materials according to their weight percentile: Linaloyl acetate 20%-30%, linalool 15%-25%, limonene 5%-10%, patchouli alcohol 3%-5%, sandalwood alcohol 3%-5%, citronellol 1%-3%, Ashwagandha essential oil 35%-40%; The compound essential oil was completely dissolved in anhydrous ethanol to form a clear essential oil ethanol solution, thus obtaining the essential oil core material. The concentration of the compound essential oil in the essential oil ethanol solution was 25%.

[0026] S3. Inclusion reaction: In a constant temperature water bath, the essential oil core material is slowly added to the wall material solution, the temperature of the reaction system is controlled at 50~60°C, and the mixture is continuously mechanically stirred at a speed of 150~200 rpm for 2.5 h to ensure sufficient molecular inclusion and obtain the reaction solution.

[0027] S4. Post-processing: The reaction solution was first allowed to stand at room temperature (25°C) for 1.5 h until initial crystals appeared. Then, 20 mL of anhydrous ethanol was added and stirred for 10 min. The mixture was then transferred to an ice-water bath and cooled for 2–2.5 h to allow complete precipitation. The precipitate was obtained by filtration and washed twice with cold water. For deep purification, the precipitate was redispersed in 50–100 mL of cold deionized water, sonicated for 5 min, and then centrifuged at 3000–4000 rpm for 5–10 min. The supernatant was discarded, and the centrifugation and washing were repeated twice. Finally, the purified wet microcapsules were dried in a 40°C oven for 4 h to constant weight. After grinding, the dried compound essential oil microcapsule powder was obtained.

[0028] This invention utilizes β-cyclodextrin to encapsulate essential oil components at the molecular level, forming stable inclusion microcapsules. This process is not a simple physical mixing, but rather an encapsulation based on host-guest chemistry, which significantly improves the thermal stability and antioxidant properties of essential oils.

[0029] This invention, through its method for preparing compound essential oil microcapsule powder, fundamentally solves the problems of essential oil volatility and oxidation. Microencapsulation isolates the essential oil from the external environment, ensuring product stability and shelf life during storage. Simultaneously, the release of the essential oil must undergo a diffusion process from the β-cyclodextrin cavity, forming the first slow-release barrier and smoothing the release process. The microcapsule structure of the compound essential oil microcapsule powder protects the essential oil from the influence of nasal pH or enzymes, reducing the rate of biodegradation.

[0030] (2) Preparation of a hydrogel matrix, wherein the hydrogel matrix is ​​chitosan-β-glycerophosphate sodium, a smart gel carrier capable of undergoing a phase transition at body temperature. Specifically, this includes the following steps: S1. Accurately weigh chitosan powder and slowly add it to a 2% (w / w) glacial acetic acid solution. Stir magnetically until completely dissolved to obtain a transparent, viscous chitosan solution; wherein, the concentration of the chitosan solution is 2%. S2. Weigh out sodium β-glycerophosphate, dissolve it in phosphate buffer, filter to remove bacteria, and obtain a cross-linking agent solution. The pH of the phosphate buffer is 7.4, and the concentration of sodium β-glycerophosphate is 56% (w / v). S3. Cool the chitosan solution in an ice bath while maintaining stirring. Using a constant flow pump, slowly add the crosslinking agent solution dropwise at a precise rate of 1 mL / min. The volume ratio of chitosan solution to crosslinking agent solution is 3:1. After the addition is complete, continue stirring in the ice bath for 30 min to obtain a homogeneous hydrogel matrix that is flowable at low temperature. Optionally, add 0.1%-0.5% (v / v) of Tween 80 and adjust the pH to 6.5-7.0 to optimize its olfactory properties and biocompatibility. It should be noted that Tween 80 is not a component of the hydrogel matrix; its function is to optimize the olfactory properties and biocompatibility of the hydrogel matrix. In actual production applications, Tween 80 can be omitted.

[0031] This invention utilizes a chitosan / sodium β-glycerophosphate system to construct a thermosensitive hydrogel. This system is a flowable sol at low temperatures, facilitating mixing and dispensing with microcapsules; upon contact with the temperature of the human nasal cavity (approximately 32-34°C), it rapidly undergoes a sol-gel phase transition, forming a stable three-dimensional network structure.

[0032] The preparation method of the hydrogel matrix of this invention achieves the function of "triggering lock-in upon use". On the one hand, the gel network constitutes a second physical barrier for the microcapsules dispersed therein, further regulating the diffusion rate of essential oils and achieving long-lasting release (target of more than 24 hours). On the other hand, the gel matrix itself has good biocompatibility and moisturizing properties, improving the safety and nasal comfort of use.

[0033] (3) Preparation of nasal inhaler: by mass percentage, the compound essential oil microcapsule powder is 5-15%, and the hydrogel matrix is ​​85-95%; The compound essential oil microcapsule powder was mixed with the hydrogel matrix under ice bath conditions of 4-8°C at a stirring speed of 100-200 rpm for 15-30 min to obtain a nasal inhaler.

[0034] The nasal inhaler of this invention possesses excellent scalability and customization potential. By adjusting the aforementioned parameters according to different users' fragrance preferences or sleep-inducing strength needs, personalized products with subtle differences can be prepared, providing a material basis for precise sleep aids.

[0035] The second thing this invention aims to protect is the nasal inhaler obtained by the above preparation method.

[0036] The third aspect of this invention is the application of the aforementioned nasal inhaler in the preparation of nasal inhalation products. The specific method for this application is as follows: After the nasal inhaler is prepared, it is placed in an ice bath for a few minutes to remove air bubbles, and then quantitatively dispensed into sterile, sealed nasal inhaler containers at room temperature; the dispensed product is then stored at 4°C. When used, the nasal inhaler is removed, and upon contact with the nasal cavity temperature (approximately 32-34°C), the nasal inhaler rapidly transforms into a non-flowing gel state within 1-3 minutes, and begins to continuously and steadily release sleep-inducing aroma components.

[0037] The preparation processes (mixing and dispensing) of the nasal inhaler and nasal inhalation products of this invention are all completed under ice bath low-temperature conditions (4-8°C) to ensure that the hydrogel matrix is ​​in the liquid processing window; while the nasal inhalation products function at nasal cavity temperature to achieve gelation and sustained release initiation.

[0038] The preparation method described in this invention ingeniously resolves the contradiction between processing feasibility and usage effectiveness. Low-temperature processing ensures that the microcapsules can be uniformly dispersed without rupture, and also facilitates precise filling; body temperature triggering ensures that the product only activates its optimal sustained-release structure when used, achieving an intelligent "on-demand" effect and avoiding performance loss during transportation and storage.

[0039] <Example 1> A method for preparing a long-acting sustained-release nasal inhaler combining microencapsulation and hydrogel technologies includes the following steps: (1) Preparation of compound essential oil microcapsule powder, specifically including the following steps: S1. Preparation of wall material solution: Accurately weigh 80.0g of β-cyclodextrin, add it to 450 mL of deionized water, heat to 120°C and stir at high speed to completely dissolve it to form a homogeneous and transparent solution, then cool it to 80°C for later use to obtain the wall material solution; S2. Preparation of essential oil core material: Prepare a total weight of 10.0 g of sleep-aiding compound essential oil according to the following precise mass percentages: 2.45 g linalyl acetate, 1.85 g linalool, 0.78 g limonene, 0.50 g patchouli alcohol, 0.30 g sandalwood alcohol, 0.20 g citronellol, and 3.89 g Ashwagandha essential oil. Dissolve the compound essential oil completely in 30 mL anhydrous ethanol to form a clear essential oil ethanol solution. S3. Inclusion reaction: In a constant temperature water bath, the essential oil core material is slowly added to the wall material solution, the temperature of the reaction system is controlled at 50~60°C, and the mixture is continuously mechanically stirred at a speed of 150~200 rpm for 2.5 h to ensure sufficient molecular inclusion and obtain the reaction solution. S4. Post-processing: The reaction solution was first allowed to stand at room temperature (25°C) for 1.5 h until initial crystals appeared. Then, 20 mL of anhydrous ethanol was added and stirred for 10 min. The mixture was then transferred to an ice-water bath and cooled for 2–2.5 h to allow complete precipitation. The precipitate was obtained by filtration and washed twice with cold water. For deep purification, the precipitate was redispersed in 50–100 mL of cold deionized water, sonicated for 5 min, and then centrifuged at 3000–4000 rpm for 5–10 min. The supernatant was discarded, and the centrifugation and washing were repeated twice. Finally, the purified wet microcapsules were dried in a 40°C oven for 4 h to constant weight. After grinding, the dried compound essential oil microcapsule powder was obtained.

[0040] (2) Preparation of a hydrogel matrix, which is a smart gel carrier capable of undergoing a phase transition at body temperature; specifically including the following steps: S1. Accurately weigh 1.0g of chitosan powder and slowly add it to 50 mL of 2% glacial acetic acid solution. Stir magnetically until completely dissolved to obtain a transparent and viscous chitosan solution. S2. Weigh 5.6g of sodium β-glycerophosphate, dissolve it in 10mL of phosphate buffer, filter to remove bacteria, and obtain a cross-linking agent solution; S3. Cool the chitosan solution in an ice bath while maintaining stirring. Using a constant flow pump, slowly add the cross-linking agent solution dropwise at a precise rate of 1 mL / min. The volume ratio of chitosan solution to cross-linking agent solution is 3:1. After the addition is complete, continue stirring in the ice bath for 30 min to obtain a homogeneous hydrogel matrix that is flowable at low temperature. Optionally, add 0.2 mL of Tween 80 and adjust the pH to 7.0 to optimize its olfactory properties and biocompatibility.

[0041] (3) Preparation of nasal inhaler: by mass percentage, the compound essential oil microcapsule powder is 15% and the hydrogel matrix is ​​85%; The compound essential oil microcapsule powder was mixed with the hydrogel matrix under ice bath conditions of 4-8°C at a stirring speed of 100-200 rpm for 15-30 min to obtain a nasal inhaler.

[0042] The properties of the hydrogel matrix prepared in this embodiment were measured, and the steps are as follows: a) Sample preparation Take 5 mL of the prepared hydrogel matrix solution and pre-cool it in a 4°C refrigerator for at least 30 minutes.

[0043] b) Observe gelation Transfer the above solution to room temperature (approximately 25°C) or a 37°C water bath, observe and record the time required for it to change from liquid to gel (3 minutes and 27 seconds). Phenomenon: The surface is elastic when lightly flicked with a finger, and there is a noticeable "stringy" phenomenon when pulled.

[0044] c) Reconstitution test The gel was refrigerated overnight at 4°C. It was removed the next day and returned to a flowing liquid state. This demonstrates that the system is a reversible, thermosensitive hydrogel, suitable for nasal administration and subsequent excretion via nasal mucus.

[0045] In vitro release assay of compound essential oil microcapsule powder Experimental conditions: The receiving medium was 40% ethanol solution, and the constant temperature water bath was 37℃±0.5℃.

[0046] pH adjustment: Used to adjust the pH of the receiving medium to 7.4 (simulating the physiological environment).

[0047] Control group: Take an appropriate amount of essential oil core material (10mg) obtained in step S2 of step (1) of this embodiment, place it in a 10mL volumetric flask, add about 5mL of anhydrous ethanol and extract by ultrasonic extraction for 30min until completely dissolved, dilute to the mark with mobile phase (40% ethanol) and shake well.

[0048] At this time, the solution concentration ,in To weigh the sample, This is the constant volume.

[0049] (1) Pretreatment of dialysis bags Cut the dialysis bag to 12-15cm and soak it in distilled water for at least 4 hours.

[0050] Purpose: To remove the preservative solution (usually glycerin) from the factory to prevent it from interfering with subsequent media.

[0051] Place the soaked dialysis bag in a beaker, add enough distilled water, and boil for 10-15 minutes. Remove the bag immediately after boiling to avoid over-boiling, which could cause the dialysis bag to become brittle or break.

[0052] Rinse the dialysis bag repeatedly with distilled water until the outflowing water is clear, transparent, and odorless.

[0053] (2) Sample loading and sealing: Weigh 20 mg of the compound essential oil microcapsule powder prepared in Example S4 after spray drying, put the compound essential oil microcapsule powder into a dialysis bag, remove the air, tie the two ends together (or use clips to tighten) to ensure a tight seal and prevent the compound essential oil microcapsule powder from leaking out.

[0054] (3) Medium preparation and balancing: Prepare 50 mL of PBS buffer (pH 6.8), add 0.25 mL of Tween 80 (i.e., 0.5% concentration), vortex to mix, and obtain PBS / Tween 80 solution.

[0055] The dialysis bag containing the compound essential oil microcapsule powder was completely immersed in the above solution.

[0056] (4) Isothermal release: Place the centrifuge tube containing the dialysis bag into a 37°C isothermal shaker and set the speed to 50-100 rpm (simulating nasal mucosal peristalsis).

[0057] (5) Stop incubation: Remove the centrifuge tube containing the dialysis bag from the 37°C constant temperature shaker.

[0058] (6) Settling: Let the test tube stand at room temperature for 10-15 minutes. Use gravity to allow the compound essential oil microcapsule powder to slowly settle to the bottom, avoiding damage to the dialysis bag caused by violent shaking during subsequent operations.

[0059] (7) Careful sampling: Use a pipette to carefully aspirate about 1 mL of clear PBS buffer from the top layer of the centrifuge tube solution and transfer this liquid to another clean centrifuge tube for storage. Insert the pipette tip vertically about 1 cm below the liquid surface and slowly and evenly discharge the liquid. The operation should be gentle, and try not to touch the sediment at the bottom of the tube to prevent microcapsules from adhering to the tube wall.

[0060] (8) Refilling and rehydration: Take out the test tube and add 1 mL of fresh PBS / Tween80 to the bottom of the test tube from step (6). Gently blow or invert to mix and resuspend the microcapsules. Then put the test tube back into the constant temperature shaker to continue incubation.

[0061] (9) Composition determination: Take a clean centrifuge tube, add 1 mL of PBS supernatant from the test tube in step (8), then add 1 mL of anhydrous diethyl ether, and vortex vigorously for 1 minute to mix the two phases thoroughly. Let it stand at room temperature for about 5-10 minutes to separate the phases. The upper layer is the organic phase (containing essential oils), and the lower layer is the aqueous phase. Carefully transfer the upper organic phase (about 0.8-1 mL) to another small test tube.

[0062] (10) The upper organic phase was sampled and subjected to GC analysis to plot the cumulative release curve.

[0063] Depend on Figure 1As can be seen, the compound essential oil microcapsule powder prepared in this embodiment exhibits a gradual upward trend in the first 2-4 hours, followed by a continuous increase until 12 hours, maintaining the release of active ingredients. This verifies that the high density and low permeability of the microcapsule wall material (such as β-cyclodextrin or chitosan) can effectively control the drug release rate and prevent burst release. In practical use, it should be able to achieve the ideal state of "rapid onset of action + long-lasting effect". The sustained-release characteristics of the microcapsules allow the essential oil components to be continuously released on the nasal mucosa surface. Unlike traditional single-use sprays, the nasal inhaler prepared using the nasal inhaler of this embodiment can overcome the clearance mechanism of the nasal mucosa (such as ciliary movement), maintaining a longer duration of efficacy, which meets the requirements of sleep aid preparations.

[0064] Tests showed that the essential oil encapsulation rate of the nasal inhaler prepared in this embodiment was 85%, indicating that the essential oil components did not undergo significant volatilization loss or oxidation during the preparation process, thus ensuring the integrity of the active substances.

[0065] <Example 2> A method for preparing a long-acting sustained-release nasal inhaler combining microencapsulation and hydrogel technologies includes the following steps: (1) Preparation of compound essential oil microcapsule powder, specifically including the following steps: S1. Preparation of wall material solution: Accurately weigh 80.0g of β-cyclodextrin, add it to 450 mL of deionized water, heat to 120°C and stir at high speed to completely dissolve it to form a homogeneous and transparent solution, then cool it to 80°C for later use to obtain the wall material solution.

[0066] S2. Preparation of essential oil core material: Prepare a total weight of 10.0 g of sleep-aiding compound essential oil according to the following precise mass percentages: 2.5 g linalyl acetate, 2.00 g linalool, 0.80 g limonene, 0.30 g patchouli alcohol, 0.35 g santalol, 0.25 g citronellol, and 3.80 g Ashwagandha essential oil. Completely dissolve this compound essential oil in 30 mL anhydrous ethanol to form a clear essential oil ethanol solution.

[0067] S3. Inclusion reaction: In a constant temperature water bath, the essential oil core material is slowly added to the wall material solution, the temperature of the reaction system is controlled at 50~60°C, and the mixture is continuously mechanically stirred at a speed of 150~200 rpm for 2.5 h to ensure sufficient molecular inclusion and obtain the reaction solution.

[0068] S4. Post-processing: The reaction solution was first allowed to stand at room temperature (25°C) for 1.5 h until initial crystals appeared. Then, 20 mL of anhydrous ethanol was added and stirred for 10 min. The mixture was then transferred to an ice-water bath and cooled for 2–2.5 h to allow complete precipitation. The precipitate was obtained by filtration and washed twice with cold water. For deep purification, the precipitate was redispersed in 50–100 mL of cold deionized water, sonicated for 5 min, and then centrifuged at 3000–4000 rpm for 5–10 min. The supernatant was discarded, and the centrifugation and washing were repeated twice. Finally, the purified wet microcapsules were dried in a 40°C oven for 4 h to constant weight. After grinding, the dried compound essential oil microcapsule powder was obtained.

[0069] (2) Preparation of a hydrogel matrix, which is a smart gel carrier capable of undergoing a phase transition at body temperature. Specifically, this includes the following steps: S1. Accurately weigh 1.0g of chitosan powder and slowly add it to 50 mL of 2% glacial acetic acid solution. Stir magnetically until completely dissolved to obtain a transparent and viscous chitosan solution. S2. Weigh 5.6g of sodium β-glycerophosphate, dissolve it in 10mL of phosphate buffer, filter to remove bacteria, and obtain a cross-linking agent solution; S3. Cool the chitosan solution in an ice bath while maintaining stirring. Using a constant flow pump, slowly add the cross-linking agent solution dropwise at a precise rate of 1 mL / min. The volume ratio of chitosan solution to cross-linking agent solution is 3:1. After the addition is complete, continue stirring in the ice bath for 30 min to obtain a homogeneous hydrogel matrix that is flowable at low temperature. Optionally, add 0.1 mL of Tween 80 and adjust the pH to 7.0 to optimize its olfactory properties and biocompatibility.

[0070] (3) Preparation of nasal inhaler: by mass percentage, the compound essential oil microcapsule powder is 10% and the hydrogel matrix is ​​90%; The compound essential oil microcapsule powder was mixed with the hydrogel matrix under ice bath conditions of 4-8°C at a stirring speed of 100-200 rpm for 15-30 min to obtain a nasal inhaler.

[0071] While the present invention has been disclosed above, its scope of protection is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of this disclosure, and all such changes and modifications will fall within the scope of protection of this invention.

Claims

1. A method for preparing a long-acting sustained-release nasal inhaler for sleep aid combining microencapsulation technology and hydrogel technology, characterized in that, Includes the following steps: S1. Preparation of compound essential oil microcapsule powder; S2. Preparation of hydrogel matrix; S3, by weight percentage, the compound essential oil microcapsule powder is 5-15%, and the hydrogel matrix is ​​85-95%; The compound essential oil microcapsule powder was mixed with the hydrogel matrix under ice bath conditions of 4-8℃, with a mixing speed of 100-200 rpm and a time of 15-30 min to obtain a nasal inhaler.

2. The method for preparing a long-acting sustained-release sleep aid nasal inhaler combining microencapsulation technology and hydrogel technology according to claim 1, characterized in that, In step S1, the specific method for preparing the compound essential oil microcapsule powder is as follows: S11. Preparation of wall material solution: Accurately weigh β-cyclodextrin, add it to deionized water and dissolve it to obtain the wall material solution; S12. Preparation of essential oil core material: Linaloyl acetate, linalool, limonene, patchouli alcohol, sandalwood alcohol, citronellol, and ashwagandha essential oil are mixed and dissolved in anhydrous ethanol to form a clear essential oil ethanol solution, thus obtaining the essential oil core material. S13. The essential oil core material is added to the wall material solution to carry out an inclusion reaction, and a reaction solution is obtained. S14. The reaction solution is subjected to standing, precipitation, washing, centrifugation, purification, drying and grinding in sequence to obtain compound essential oil microcapsule powder.

3. The method for preparing a long-acting sustained-release sleep aid nasal inhaler combining microencapsulation technology and hydrogel technology according to claim 2, characterized in that, In step S11, the concentration of β-cyclodextrin is 177.8 g / L.

4. The method for preparing a long-acting sustained-release sleep aid nasal inhaler combining microencapsulation technology and hydrogel technology according to claim 2, characterized in that, In step S12, the following components are present in mass percentile: 20%-30% linaloacetate, 15%-25% linalool, 5%-10% limonene, 3%-5% patchouli alcohol, 3%-5% sandalwood alcohol, 1%-3% citronellol, and 35%-40% ashwagandha essential oil.

5. The method for preparing a long-acting sustained-release sleep aid nasal inhaler combining microencapsulation technology and hydrogel technology according to claim 2, characterized in that, In step S13, the mixing ratio of the essential oil core material to the wall material solution is 1:

15.

6. The method for preparing a long-acting sustained-release sleep aid nasal inhaler combining microencapsulation technology and hydrogel technology according to claim 1, characterized in that, In step S2, the specific steps for preparing the hydrogel matrix are as follows: S21. Accurately weigh the chitosan powder and slowly add it to a 2% (w / w) glacial acetic acid solution. Stir magnetically until completely dissolved to obtain a transparent and viscous chitosan solution. S22. Weigh out sodium β-glycerophosphate, dissolve it in phosphate buffer, filter to remove bacteria, and obtain a cross-linking agent solution; S23. Cool the chitosan solution in an ice bath while stirring, and add the crosslinking agent solution at a dropping rate of 1 mL / min. After the addition is complete, continue stirring in the ice bath for 30 min to obtain the hydrogel matrix.

7. The method for preparing a long-acting sustained-release sleep aid nasal inhaler combining microencapsulation technology and hydrogel technology according to claim 5, characterized in that, In step S21, the concentration of the chitosan solution is 2%; In step S22, the concentration of sodium β-glycerophosphate is 56% (w / v); In step S23, the volume ratio of chitosan solution to crosslinking agent solution is 3:

1.

8. A long-acting sustained-release sleep aid nasal inhaler is obtained by the preparation method according to any one of claims 1-7.

9. The use of the long-acting sustained-release sleep aid nasal inhaler as described in claim 8 in the preparation of nasal inhalation products.

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