Natural polysaccharide temperature-sensitive gel for freeing lung and reducing phlegm for children and preparation method of natural polysaccharide temperature-sensitive gel

Abstract

The invention belongs to the technical field of traditional Chinese medicine preparations, and particularly relates to a natural polysaccharide temperature-sensitive gel for freeing lung and reducing phlegm for children and a preparation method thereof.The natural polysaccharide temperature-sensitive gel is prepared from, by weight, 3-8 parts of traditional Chinese medicine nano-composites, 16-20 parts of poloxamer 407 and 0.6-1.2 parts of low-acyl gellan gum, the preparation method comprises the following steps: taking traditional Chinese medicine extracts of perilla leaves, bitter apricot kernels, platycodon grandiflorum and liquorice as a core, forming a nano-composite through astragalus polysaccharide and hydroxypropyl-beta-cyclodextrin, and finally loading the nano-composite into a temperature-sensitive gel network constructed by low-acyl gellan gum and poloxamer 407. The constructed natural polysaccharide temperature-sensitive gel not only can effectively mask the unpleasant odor of the medicine and improve the stability of the medicine, but also can remarkably prolong the residence time of the medicine in the nasal cavity, so that the long-acting treatment effect of ventilating the lung and reducing phlegm is realized.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine preparation technology, specifically relating to a natural polysaccharide thermosensitive gel for children to relieve lung congestion and phlegm, and its preparation method. Background Technology

[0002] Children's respiratory systems are not fully developed and are susceptible to external pathogens, often leading to impaired lung function, clinically manifesting as symptoms such as cough and excessive phlegm. Traditional Chinese medicine oral liquids or granules have a pungent smell and bitter taste, resulting in poor medication compliance in children and making it difficult to achieve the desired therapeutic effect.

[0003] The nasal mucosa is richly vascularized and highly permeable, making it a suitable non-invasive route of drug delivery that allows for synergistic local action and systemic absorption while avoiding the first-pass effect of the liver. However, conventional nasal drops and sprays are low-viscosity solutions, easily affected by ciliary clearance, mucus flow, and body position, resulting in short retention times and requiring frequent administration. While adding synthetic polymers to enhance adhesion can prolong retention, it may inhibit ciliary movement or cause mucosal dryness and irritation, leading to poor tolerance in children.

[0004] Furthermore, the active ingredients in lung-clearing and phlegm-resolving drugs, such as perilla leaves and bitter almonds, contain volatile oils. These ingredients are highly irritating to the nasal mucosa and can easily induce a sneezing reflex or discomfort. At the same time, volatile oils are chemically unstable, posing risks of oxidation and volatilization, and their release behavior is difficult to control. More importantly, formulation design often focuses on physical masking, neglecting the logic of traditional Chinese medicine compatibility: lung-clearing drugs are pungent and dispersing; without tonifying ingredients to harmonize them, long-term use may deplete the lung and spleen qi in children.

[0005] Therefore, developing a nasal delivery formulation that possesses thermosensitive response and physiological temperature adaptability, volatile oil stability and sensory comfort, mucosal biocompatibility, and rational compatibility with traditional Chinese medicine is a technical problem that urgently needs to be solved in the field of pediatric traditional Chinese medicine preparations. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a natural polysaccharide thermosensitive gel for pediatric lung-clearing and phlegm-resolving purposes and its preparation method. The natural polysaccharide thermosensitive gel uses lung-clearing and phlegm-resolving drugs as its core, constructs an Astragalus polysaccharide-volatile oil nano-delivery system, and further encapsulates it in a thermosensitive gel network, achieving synergistic optimization in terms of gel thermosensitive responsiveness, sensory comfort, rational drug delivery, mucosal retention effectiveness, and rationality of traditional Chinese medicine compatibility.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] This invention provides a natural polysaccharide thermosensitive gel for children to relieve lung congestion and phlegm. The natural polysaccharide thermosensitive gel comprises the following raw materials in parts by weight: 3-8 parts of traditional Chinese medicine nanocomposite, 16-20 parts of poloxamer 407, 0.6-1.2 parts of low acyl gellan gum, 0.2-1 parts of sodium hyaluronate, and 0.5-3 parts of isotonicity regulator.

[0009] Furthermore, the traditional Chinese medicine nanocomposite comprises the following raw materials: perilla leaf, bitter almond, platycodon root, licorice, astragalus polysaccharide and hydroxypropyl-β-cyclodextrin, wherein the mass ratio of perilla leaf, bitter almond, platycodon root, licorice, astragalus polysaccharide and hydroxypropyl-β-cyclodextrin is 3:2:3:2:2:5.

[0010] The preparation method of the traditional Chinese medicine nanocomposite includes the following steps:

[0011] S1: Weigh out perilla leaves and bitter almonds, crush them separately, sieve them, mix them evenly to obtain a mixed powder, extract them by steam distillation, collect the distillate, let it stand to separate into layers, filter it to obtain a mixed volatile oil and distillation residue, filter the distillation residue to obtain distillation residue.

[0012] S2: Weigh out licorice and platycodon, crush them and sieve them, combine them with the distilled residue, add sterile water for injection, mix them evenly to obtain an aqueous extract mixture, and then decoct, filter and concentrate under reduced pressure to obtain a concentrated liquid.

[0013] S3: Weigh hydroxypropyl-β-cyclodextrin and astragalus polysaccharide, dissolve them in sterile water for injection to obtain inclusion carrier solution, slowly add mixed volatile oil to inclusion carrier solution, and emulsify by ultrasonication to obtain inclusion premix solution;

[0014] S4: The concentrated medicinal solution is slowly added dropwise to the inclusion premix solution, and then homogenized under high pressure to obtain a nano suspension. Finally, the solution is freeze-dried to obtain the traditional Chinese medicine nanocomposite.

[0015] Furthermore, the bitter almonds are processed products that have undergone enzyme inactivation treatment by blanching.

[0016] Furthermore, the isotonic regulator is selected from any one of sodium chloride, glycerol, and sorbitol.

[0017] This invention also provides a method for preparing a natural polysaccharide thermosensitive gel for pediatric lung-clearing and phlegm-reducing purposes, specifically including the following steps:

[0018] Step 1: Weigh 16-20 parts of poloxamer 407, slowly disperse it in pre-cooled sterile water for injection, and let it stand to allow it to swell fully to obtain a poloxamer 407 solution. Weigh 0.6-1.2 parts of low-acyl gellan gum, slowly disperse it in sterile water for injection, heat it to completely dissolve it, and cool it to obtain a gellan gum solution.

[0019] Step 2: Slowly add the gellan gel solution dropwise into the poloxamer 407 solution, and let it stand at low temperature to eliminate air bubbles, thus obtaining a thermosensitive gel matrix;

[0020] Step 3: Weigh 0.2-1 parts of sodium hyaluronate and dissolve it evenly in sterile water for injection to obtain an adhesive solution. Weigh 0.5-3 parts of isotonicity regulator and dissolve it evenly in sterile water for injection to obtain an excipient solution. Add the adhesive solution to the excipient solution to obtain an additive solution.

[0021] Step 4: Weigh 3-8 parts of the traditional Chinese medicine nanocomposite, disperse it in sterile water for injection, and sonicate it to obtain a suspension. Slowly add the suspension to the thermosensitive gel matrix, mix it evenly, slowly add the additive solution and add sterile water for injection to the specified volume to obtain the gel precursor.

[0022] Step 5: Allow the gel precursor to stand and age, then degas it under vacuum and dispense it into individual containers to obtain a natural polysaccharide thermosensitive gel for children to clear the lungs and resolve phlegm.

[0023] The beneficial effects achieved by this invention are as follows:

[0024] This invention constructs a gel network with dual thermosensitive properties by introducing low-acyl gellan gum in synergy with poloxamer 407. Low-acyl gellan gum, an anionic natural polysaccharide, forms a thermally irreversible gel backbone under the influence of cationic reactions in the system. This backbone complements the thermally reversible gelling properties of poloxamer 407, significantly enhancing the mechanical strength and structural stability of the gel. Simultaneously, it allows for precise control of the gelation temperature, enabling the formulation to maintain good fluidity at low temperatures for easy administration. Upon contact with the nasal cavity temperature, it rapidly forms a uniform and dense gel structure, effectively ensuring in-situ retention and morphological integrity at the site of action after administration.

[0025] This invention constructs an Astragalus polysaccharide-volatile oil nanodelivery system. Using Astragalus polysaccharide extracted from the herb itself as the carrier material, a high-pressure homogenization process is employed to encapsulate volatile components such as perillaldehyde and platycodon oil, which promote lung function and resolve phlegm, into nanoparticles for drug delivery. On one hand, the polysaccharide wall material physically blocks the pungent and bitter taste of the volatile oil, effectively improving the aroma and taste of the preparation and significantly enhancing pediatric acceptance. On the other hand, this nanostructure significantly improves the stability of the volatile oil, preventing oxidation or volatilization during storage. Astragalus polysaccharide possesses the effects of tonifying qi and strengthening the exterior, enhancing immunity. Combined with other lung-clearing and phlegm-resolving herbs such as perilla leaf and bitter almond, it forms a synergistic effect of both tonifying and purging, strengthening the therapeutic effect of resolving phlegm and relieving cough while preventing the herbs from being too cold and damaging the child's vital energy, embodying the treatment philosophy of addressing both the symptoms and the root cause.

[0026] Introducing sodium hyaluronate as a bioadhesive component, its abundant carboxyl and hydroxyl groups on its molecular chain can form multiple hydrogen bonds and van der Waals forces with glycoproteins on the respiratory mucosa surface, significantly enhancing the adhesion strength and persistence of the gel at the mucosal interface. This prolongs the drug's residence time at the site of action, achieving stable sustained release and reducing the frequency of administration, making it particularly suitable for clinical needs requiring sustained nighttime efficacy to relieve cough symptoms during sleep in children.

[0027] The natural polysaccharide thermosensitive gel designed in this invention achieves synergistic optimization in thermoresponsiveness, rational drug delivery, and effective mucosal retention, providing a new nasal local drug delivery strategy for children's lung-clearing and phlegm-reducing purposes that is accurate in positioning, convenient to use, and has high compliance. Attached Figure Description

[0028] Figure 1 The results of the volatile oil retention rate test of the natural polysaccharide thermosensitive gels prepared in Example 2 and Comparative Example 3;

[0029] Figure 2 The results of in vitro release tests of perillaldehyde in the natural polysaccharide thermosensitive gels prepared in Example 2 and Comparative Examples 1-3 are shown.

[0030] Figure 3 The results of in vitro release tests of amygdalin from the natural polysaccharide thermosensitive gels prepared in Example 2 and Comparative Examples 1-3 are shown. Detailed Implementation

[0031] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention. The preferred embodiments and materials described herein are for illustrative purposes only and do not limit the scope of this application.

[0033] Unless otherwise specified, all methods used in the following examples are conventional. Unless otherwise specified, all materials used in the following examples are new materials purchased from the market. The Chinese medicinal herbs used, including Perilla Leaf, Bitter Almond, Platycodon Root, and Licorice Root, are all standard processed medicinal materials according to the Chinese Pharmacopoeia. The hydroxypropyl-β-cyclodextrin, Astragalus Polysaccharide, Poloxamer 407, Low-Acyl Gellan Gel, Sorbitol, Sodium Chloride, and Glycerin used all meet the standards of the Chinese Pharmacopoeia. Specifically, the hydroxypropyl-β-cyclodextrin is pharmaceutical grade, with an average degree of substitution of 0.8, moisture content ≤10.0%, and heavy metal content ≤10 ppm; the Astragalus Polysaccharide is pharmaceutical grade, with a polysaccharide content ≥70% and moisture content ≤8.0%; the Poloxamer 407 is pharmaceutical grade, with a molecular weight of approximately 12600 g / mol and a polyoxyethylene content of approximately 70%; and the Low-Acyl Gellan Gel is pharmaceutical grade, with an acyl content ≤30% and a gel strength ≥800 g / cm³. 2 The sorbitol is pharmaceutical grade, with a purity ≥98.0% and moisture content ≤1.5%; the sodium chloride is pharmaceutical grade, with a purity ≥99.0% and heavy metal content ≤10 ppm; the glycerol is pharmaceutical grade, with a purity ≥98.0% and moisture content ≤2.0%; the sodium hyaluronate is pharmaceutical grade, with a purity ≥95% and microbial limits meeting the requirements.

[0034] Example 1: This example provides a natural polysaccharide thermosensitive gel for children to clear the lungs and resolve phlegm. The natural polysaccharide thermosensitive gel includes the following raw materials in parts by weight: 3 parts of traditional Chinese medicine nanocomposite, 16 parts of poloxamer 407, 0.8 parts of low acyl gellan gum, 0.8 parts of sodium hyaluronate, and 0.75 parts of sorbitol.

[0035] The traditional Chinese medicine nanocomposite comprises the following raw materials in parts by weight: 3 parts perilla leaf, 2 parts bitter almond, 3 parts platycodon, 2 parts licorice, 2 parts astragalus polysaccharide, and 5 parts hydroxypropyl-β-cyclodextrin.

[0036] The preparation method of the traditional Chinese medicine nanocomposite includes the following steps:

[0037] S1: Weigh 3 parts of perilla leaves and 2 parts of bitter almonds, pulverize them separately and pass them through an 80-mesh sieve, mix them evenly to obtain a mixed powder, put it into a round-bottom flask, add 10 times the amount (based on the total weight of the medicinal materials) of sterile water for injection, extract by steam distillation for 3 hours, collect the distillate, let it stand at 4℃ for 12 hours and filter it, collect the upper oil phase to obtain mixed volatile oil, filter the distillation residue in the round-bottom flask to obtain distilled residue;

[0038] S2: Weigh 2 parts of licorice and 3 parts of platycodon, grind them separately and pass them through an 80-mesh sieve. Combine them with the distilled residue, add sterile water for injection to make the total liquid volume 8 times the total weight of the medicinal materials, mix well and obtain an aqueous extract mixture. Soak at room temperature for 1 hour, then decoct twice. The first decoction is for 1.5 hours, filtered, and the first filtrate and residue are obtained. Sterile water for injection is added to the residue again to make the total weight of the residue 6 times, and the second decoction is for 1 hour, filtered, and the second filtrate is obtained. Combine the first and second decoctions and concentrate them under reduced pressure at 60℃ and -0.09 MPa to a relative density of 1.12 (60℃) to obtain a concentrated solution.

[0039] S3: Weigh 5 parts of hydroxypropyl-β-cyclodextrin and 2 parts of astragalus polysaccharide, and dissolve them together in sterile water for injection at a mass-volume ratio of 1 g: 10 mL. Stir at 50℃ and 500 rpm for 30 minutes to obtain the inclusion carrier solution. Slowly add the mixed volatile oil dropwise to the inclusion carrier solution and emulsify it in an ice-water bath using ultrasound (300W, pulse mode) for 10 minutes to obtain the inclusion premix.

[0040] S4: Under stirring at 200 rpm, the inclusion premix is ​​slowly added dropwise to the concentrated drug solution. After mixing evenly, it is homogenized by high-pressure circulation 5 times to obtain a nano suspension. Finally, the nano suspension is freeze-dried, the dried powder is collected, and it is passed through a 100-mesh sieve to obtain the traditional Chinese medicine nanocomposite.

[0041] This embodiment also provides a method for preparing a natural polysaccharide thermosensitive gel for pediatric lung-clearing and phlegm-reducing purposes, which specifically includes the following steps:

[0042] Step 1: At 4℃ and 300 rpm, 16 parts of poloxamer 407 were slowly and evenly dispersed in 32 parts of sterile water for injection. The mixture was refrigerated and allowed to swell for 12 hours to obtain a poloxamer 407 solution. 0.8 parts of low-acyl gellan gum were weighed and slowly and evenly dispersed in 8 parts of sterile water for injection. The mixture was stirred at 85℃ and 500 rpm for 30 minutes and then cooled to 4℃ to obtain a gellan gum solution.

[0043] Step 2: At 4℃ and 300 rpm, the gellan gel solution was slowly added dropwise to the poloxamer 407 solution. After stirring for 30 minutes, it was allowed to stand at 4℃ for 12 hours to obtain the thermosensitive gel matrix.

[0044] Step 3: At room temperature and 200 rpm, weigh 0.8 parts of sodium hyaluronate and slowly and evenly disperse it in 8 parts of sterile water for injection to obtain a bioadhesive solution. Weigh 0.75 parts of sorbitol and evenly dissolve it in 4 parts of sterile water for injection to obtain an excipient solution. Add the bioadhesive solution to the excipient solution and continue stirring for 30 minutes to obtain an additive solution.

[0045] Step 4: Weigh 3 parts of the pre-cooled traditional Chinese medicine nanocomposite at 4℃ and 200 rpm, add it to 6 parts of pre-cooled sterile water for injection, disperse it by ultrasonication (200W, 3 minutes) to obtain a suspension, slowly add the suspension to the thermosensitive gel matrix, stir for 20 minutes, slowly add the pre-cooled additive solution and make up the total weight to 100 parts with pre-cooled sterile water for injection, continue stirring for 30 minutes, adjust the pH value to 6.0, and obtain the gel precursor;

[0046] Step 5: After aging the gel precursor at 4°C for 24 hours, it is degassed under vacuum at 4°C and -0.08 MPa for 10 minutes and dispensed into sterile pharmaceutical tubes to obtain a natural polysaccharide thermosensitive gel for pediatric lung clearing and phlegm reduction.

[0047] Example 2: This example provides a natural polysaccharide thermosensitive gel for children to clear the lungs and resolve phlegm. The natural polysaccharide thermosensitive gel includes the following raw materials in parts by weight: 5 parts of traditional Chinese medicine nanocomposite, 18 parts of poloxamer 407, 0.9 parts of low acyl gellan gum, 0.3 parts of sodium hyaluronate, and 0.5 parts of sodium chloride.

[0048] The preparation method of the traditional Chinese medicine nanocomposite is the same as in Example 1.

[0049] This embodiment also provides a method for preparing a natural polysaccharide thermosensitive gel for pediatric lung-clearing and phlegm-reducing purposes, which specifically includes the following steps:

[0050] Step 1: At 4℃ and 300 rpm, 18 parts of poloxamer 407 were slowly and evenly dispersed in 36 parts of sterile water for injection. The mixture was refrigerated and allowed to swell for 12 hours to obtain a poloxamer 407 solution. 0.9 parts of low-acyl gellan gum were weighed and slowly and evenly dispersed in 9 parts of sterile water for injection. The mixture was stirred at 85℃ and 500 rpm for 30 minutes and then cooled to 4℃ to obtain a gellan gum solution.

[0051] Step 2: At 4℃ and 300 rpm, the gellan gel solution was slowly added dropwise to the poloxamer 407 solution. After stirring for 30 minutes, it was allowed to stand at 4℃ for 12 hours to obtain the thermosensitive gel matrix.

[0052] Step 3: Weigh 0.3 parts of sodium hyaluronate at 200 rpm and slowly and evenly disperse it in 3 parts of sterile water for injection to obtain an adhesive solution. Weigh 0.5 parts of sodium chloride and evenly dissolve it in 3 parts of sterile water for injection to obtain an excipient solution. Add the adhesive solution to the excipient solution and continue stirring for 30 minutes to obtain an additive solution.

[0053] Step 4: Weigh 5 parts of the pre-cooled traditional Chinese medicine nanocomposite at 4℃ and 200 rpm, add it to 10 parts of pre-cooled sterile water for injection, and disperse it by ultrasonication (200W, 3 minutes) to form a suspension. Slowly add the suspension to the thermosensitive gel matrix, stir for 20 minutes, slowly add the pre-cooled additive solution and make up the total weight to 100 parts with pre-cooled sterile water for injection, continue stirring for 30 minutes, adjust the pH value to 6.0, and obtain the gel precursor.

[0054] Step 5: After aging the gel precursor at 4°C for 24 hours, degas it under vacuum at 4°C and -0.08MPa for 10 minutes, and dispense it into sterile pharmaceutical tubes to obtain a natural polysaccharide thermosensitive gel for pediatric lung clearing and phlegm reduction.

[0055] Example 3: This example provides a natural polysaccharide thermosensitive gel for children to clear the lungs and resolve phlegm. The natural polysaccharide thermosensitive gel includes the following raw materials in parts by weight: 8 parts of traditional Chinese medicine nanocomposite, 20 parts of poloxamer 407, 1 part of low acyl gellan gum, 0.5 parts of sodium hyaluronate, and 3 parts of glycerin.

[0056] The preparation method of the traditional Chinese medicine nanocomposite is the same as in Example 1.

[0057] This embodiment also provides a method for preparing a natural polysaccharide thermosensitive gel for pediatric lung-clearing and phlegm-reducing purposes, which specifically includes the following steps:

[0058] Step 1: At 4℃ and 300 rpm, 20 parts of poloxamer 407 were slowly and evenly dispersed in 40 parts of sterile water for injection. The mixture was refrigerated and allowed to swell for 12 hours to obtain a poloxamer 407 solution. One part of low-acyl gellan gum was weighed and slowly and evenly dispersed in 10 parts of sterile water for injection. The mixture was stirred at 85℃ and 500 rpm for 30 minutes and then cooled to 4℃ to obtain a gellan gum solution.

[0059] Step 2: At 4℃ and 300 rpm, the gellan gel solution was slowly added dropwise to the poloxamer 407 solution. After stirring for 30 minutes, it was allowed to stand at 4℃ for 12 hours to obtain the thermosensitive gel matrix.

[0060] Step 3: At room temperature and 200 rpm, weigh 0.5 parts of sodium hyaluronate and slowly and evenly disperse it in 5 parts of sterile water for injection to obtain an adhesive solution. Weigh 3 parts of glycerin and evenly dissolve it in 6 parts of sterile water for injection to obtain an excipient solution. Add the adhesive solution to the excipient solution and continue stirring for 30 minutes to obtain an additive solution.

[0061] Step 4: Weigh 8 parts of the pre-cooled traditional Chinese medicine nanocomposite at 4℃ and 200 rpm, add it to 16 parts of pre-cooled sterile water for injection, and disperse it by ultrasonication (200W, 3 minutes) to form a suspension. Slowly add the suspension to the thermosensitive gel matrix, stir for 20 minutes, slowly add the pre-cooled additive solution and make up the total weight to 100 parts with pre-cooled sterile water for injection, continue stirring for 30 minutes, adjust the pH value to 6.0, and obtain the gel precursor.

[0062] Step 5: After aging the gel precursor at 4°C for 24 hours, degas it under vacuum at 4°C and -0.08MPa for 10 minutes, and dispense it into sterile pharmaceutical tubes to obtain a natural polysaccharide thermosensitive gel for pediatric lung clearing and phlegm reduction.

[0063] The difference between Comparative Example 1 and Example 2 is that no low-acyl gellan gum was added; the rest is the same as Example 2.

[0064] The difference between Comparative Example 2 and Example 2 is that sodium hyaluronate was not added; the rest of the parts are the same as Example 2.

[0065] The difference between Comparative Example 3 and Example 2 is that the traditional Chinese medicine nanocomposite was not prepared by cyclodextrin inclusion and high-pressure homogenization process, but by ordinary traditional Chinese medicine extract powder. The rest of the process is the same as in Example 2.

[0066] Gelation temperature and gelation time test experiment

[0067] The natural polysaccharide thermosensitive gels prepared in Examples 1-3 and Comparative Examples 1-3 were placed in the sample cell of a rotational rheometer (n=3) and heated from 4℃ to 40℃ at a rate of 1℃ / min. The temperature at which the storage modulus (G') and loss modulus (G'') were equal was recorded as the gelation temperature. The experimental results are shown in Table 1.

[0068] The natural polysaccharide thermosensitive gels prepared in Examples 1-3 and Comparative Examples 1-3 were placed in a 34°C constant temperature water bath (simulating the surface temperature of a child's nasal cavity) (n=3), and the time it took for the liquid to change from a flowing liquid to a non-flowing gel was recorded as the gelation time. The experimental results are shown in Table 1.

[0069] Table 1. Test results of gelation temperature and gelation time

[0070]

[0071] In vitro bioadhesion test experiment

[0072] Fresh mouse nasal mucosa tissue was taken, rinsed with sterile saline, and immediately fixed onto a glass slide. The probe of the testing instrument and the environmental chamber were preheated to 34°C to simulate physiological temperature, and a high humidity environment was maintained inside the chamber. The natural polysaccharide thermosensitive gel prepared in Example 2 and Comparative Example 2 was placed between two pieces of nasal mucosa tissue, and 50 g of pressure was applied to ensure full contact. After standing for 90 seconds, the upper glass slide was moved vertically upward at a constant rate (1.0 mm / min) until the two layers of mucosa tissue were completely separated. Each experiment was repeated 6 times, and the maximum peeling force (Fmax) was read. The bioadhesion force was calculated based on the contact area. The test results are shown in Table 2.

[0073] Table 2 Results of in vitro bioadhesion test

[0074]

[0075] Volatile oil retention rate test experiment

[0076] The natural polysaccharide thermosensitive gels prepared in Example 2 and Comparative Example 3 were dispensed into sealed containers and placed in a constant temperature and humidity chamber for accelerated stability testing at 40°C and 75% relative humidity (RH). Samples were taken at months 0, 1, 2, and 3 (n=3), and the contents of perillaldehyde and benzaldehyde in the samples at each time point were determined by gas chromatography (GC). The content at month 0 was taken as 100%, and the relative retention rate at each time point was calculated. The test results are shown in […]. Figure 1 .

[0077] In vitro drug release experiment

[0078] The natural polysaccharide thermosensitive gels prepared in Examples 2 and Comparative Examples 1-3 were placed in treated dialysis bags, with both ends clamped to prevent leakage. The bags were then placed in a phosphate buffer solution at pH 6.8 and shaken at a constant temperature of 34°C. Samples were taken at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after the start of the experiment, and an equal amount of fresh medium was quickly added. After filtration, the concentrations of perillaldehyde (representing volatile oil) and amygdalin (representing water-soluble glycoside) in the samples at each time point were determined by HPLC, and the cumulative release rate (Q%) was calculated. The test results are shown in [Figure number missing]. Figure 2 and Figure 3 .

[0079] Results Analysis

[0080] Table 1 shows that the gelation temperatures of the natural polysaccharide thermosensitive gels prepared in Examples 1-3 were all in the range of 30-33℃, and the gelation time in a 34℃ constant temperature water bath was controlled between 40 and 75 seconds, which was highly compatible with the simulated surface temperature of a child's nasal cavity. However, Comparative Example 1, which did not add low-acyl gellan gum and relied solely on the thermosensitive properties of poloxamer 407, had a significantly higher gelation temperature of 34.7℃, which was higher than the surface temperature of a child's nasal cavity. In a 34℃ constant temperature water bath, it remained in a viscous liquid or an extremely fragile gel state for up to 180 seconds, and was easily destroyed by slight vibration.

[0081] Table 2 shows that the maximum peel force of the natural polysaccharide thermosensitive gel prepared in Example 2 to fresh mouse nasal mucosa tissue was 0.485 N, and the bioadhesion force was 0.121 N / cm. 2 This is significantly higher than that of Comparative Example 2 (maximum peel force of 0.203 N, bioadhesion force of 0.051 N / cm). 2 ).

[0082] Figure 1 The results showed that after 3 months, the retention rates of the two volatile oil components (perillaldehyde and benzaldehyde) in the natural polysaccharide thermosensitive gel prepared in Example 2 were still above 90%, while the retention rate of perillaldehyde in Comparative Example 3 had dropped to 60%, and the retention rate of benzaldehyde was only 55%, which was significantly lower than that in Example 2. This indicates that the cyclodextrin inclusion and high-pressure homogenization process effectively slowed down the volatilization and oxidative degradation under high temperature and high humidity conditions.

[0083] Figure 2 and Figure 3 The results showed that the natural polysaccharide thermosensitive gel prepared in Example 2 exhibited a stable and continuous release without burst release, with the cumulative release rates of perillaldehyde and amygdalin exceeding 90% in 24 hours. In contrast, Comparative Example 1, lacking low-acyl gelling gel, had a loose gel matrix and significant burst release in the early stage, with the cumulative release rate of the two components reaching approximately 30% in 0.25 hours. Later, matrix collapse led to a significantly lower release rate than Example 2, less than 80%. Comparative Example 3, lacking cyclodextrin inclusion and high-pressure homogenization, experienced burst release in the early stage (the cumulative release rates of the two components were 32.3% and 30.3% respectively in 0.25 hours), but insufficient release in the later stage resulted in a cumulative release rate of less than 85% in 24 hours.

[0084] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

[0085] The present invention and its embodiments have been described above. This description is not restrictive, and the accompanying drawings are only one embodiment of the present invention. The actual application is not limited to this. In conclusion, if those skilled in the art are inspired by this description and design similar methods and embodiments without departing from the spirit of the present invention, they should all fall within the protection scope of the present invention.

Claims

1. A natural polysaccharide thermosensitive gel for pediatric lung-clearing and phlegm-reducing purposes, characterized in that, The natural polysaccharide thermosensitive gel comprises the following raw materials in parts by weight: 3-8 parts of traditional Chinese medicine nanocomposite, 16-20 parts of poloxamer 407, 0.6-1.2 parts of low acyl gellan gum, 0.2-1 parts of sodium hyaluronate, and 0.5-3 parts of isotonicity regulator; The traditional Chinese medicine nanocomposite comprises the following raw materials: perilla leaf, bitter almond, platycodon root, licorice, astragalus polysaccharide and hydroxypropyl-β-cyclodextrin; The preparation method of the traditional Chinese medicine nanocomposite includes the following steps: S1: Crush, distill and separate the perilla leaves and bitter almonds to obtain the distillation residue and mixed volatile oil. Filter the distillation residue to obtain the distillation residue. S2: Grind licorice and platycodon into powder, combine with distilled residue, decoct, filter, and concentrate to obtain concentrated medicinal liquid; S3: Dissolve hydroxypropyl-β-cyclodextrin and astragalus polysaccharide together, add mixed volatile oil dropwise, and sonicate to obtain an inclusion premix; S4: The concentrated medicinal liquid is added dropwise into the inclusion premixed liquid, and after high-pressure homogenization and drying, the traditional Chinese medicine nanocomposite is obtained.

2. The natural polysaccharide thermosensitive gel for pediatric lung-clearing and phlegm-reducing purposes according to claim 1, characterized in that, The mass ratio of perilla leaf, bitter almond, platycodon root, licorice, astragalus polysaccharide, and hydroxypropyl-β-cyclodextrin is 3:2:3:2:2:

5.

3. The natural polysaccharide thermosensitive gel for pediatric lung-clearing and phlegm-reducing purposes according to claim 2, characterized in that, The bitter almonds are processed products that have undergone enzyme inactivation treatment by blanching.

4. The natural polysaccharide thermosensitive gel for pediatric lung-clearing and phlegm-reducing purposes according to claim 1, characterized in that, The isotonic adjuster is selected from any one of sodium chloride, glycerin, and sorbitol.

5. A method for preparing a natural polysaccharide thermosensitive gel for pediatric lung-clearing and phlegm-reducing purposes according to any one of claims 1-4, characterized in that, Specifically, the steps include the following: Step 1: Disperse and swell poloxamer 407 to obtain a poloxamer 407 solution, and dissolve low-acyl gellan gum to obtain a gellan gum solution; Step 2: Add gellan gum solution to poloxamer 407 solution to obtain a thermosensitive gel matrix; Step 3: Dissolve sodium hyaluronate to obtain an adhesive solution, dissolve the isotonicity regulator to obtain an excipient solution, and add the adhesive solution to the excipient solution to obtain an additive solution; Step 4: Disperse and sonicate the traditional Chinese medicine nanocomposite to obtain a suspension, add it to a thermosensitive gel matrix, and then add an additive solution to obtain a gel precursor; Step 5: Aged, degassed, and packaged the gel precursor to obtain a natural polysaccharide thermosensitive gel for children to clear the lungs and resolve phlegm.

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