Astragaloside iv-gallic acid conjugate, nasal temperature-sensitive gel and preparation method thereof

Abstract

The application discloses a astragaloside IV-gallic acid combination, a nose temperature-sensitive gel and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The astragaloside IV-gallic acid combination is obtained by the reaction of a hydroxyl group in an astragaloside IV molecule and a carboxyl group in a gallic acid molecule. The astragaloside IV-gallic acid combination has good water solubility, can realize the spatiotemporal co-delivery of the astragaloside IV and the gallic acid, and is convenient for playing the synergistic anti-allergy effect of the two. The astragaloside IV-gallic acid combination is further used to prepare the nose temperature-sensitive gel. The nose temperature-sensitive gel is a free-flowing liquid at room temperature of about 25 DEG C, becomes a solid-like gel after being adsorbed on the nasal mucosa, can prolong the release time of the drug, has good nasal mucosa adhesion, and prolongs the residence time of the drug in the nasal cavity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a combination of astragaloside-IV and gallic acid, a nasal temperature-sensitive gel and a preparation method thereof. BACKGROUND

[0002] Allergic rhinitis (AR) is an inflammation triggered by the immune system, usually caused by inhaling allergens such as dust, hair, pollen, etc., and is characterized by sneezing, nasal congestion, nasal itching and runny nose. AR can lead to reduced sleep quality, daytime sleepiness, fatigue, irritability, depression, cognitive or physical dysfunction, etc., and affects the quality of life of people.

[0003] AR can be treated by oral administration of drugs or by directly spraying drugs into the nasal cavity. The nasal mucosa is extremely thin, and the submucosal blood vessels are abundant. Drugs are quickly absorbed through the nasal mucosa, avoiding the first-pass effect and improving bioavailability. For drugs that can cause systemic side effects (such as hormone drugs), the site of action is more specific when administered nasally, greatly reducing the side effects on other systems and organs of the body. The symptoms of AR, such as nasal congestion and nasal discharge, can adversely affect life and require rapid relief of symptoms. Nasal administration can largely meet the needs of patients.

[0004] Although nasal administration has great advantages, the clearance of nasal cilia has a certain hindering effect on drug absorption, so that the residence time of general preparations in the nasal cavity is relatively short. Nasal sprays, nasal suspensions, and nasal gels are commonly used for nasal delivery of drugs to treat allergic rhinitis. Nasal sprays are liquid when sprayed and remain liquid when adsorbed on the nasal mucosa, which has a large degree of mobility, causing some of the drugs to flow to the throat during use. This part of the drug will be subject to the first-pass effect, reducing bioavailability, and causing discomfort in the throat of the patient, reducing compliance. For poorly soluble drugs, nasal suspensions can be prepared, but the drug often cannot be fully dissolved in nasal fluid before being cleared, resulting in drug loss. Drugs can also be loaded into gels and evenly applied to the nasal mucosa, but this method requires the use of cotton swabs and other tools, and it is difficult to determine the dose. Therefore, there is a need to develop a preparation that can be evenly sprayed in liquid form on the nasal mucosa and better adsorbed on the nasal mucosa when it comes into contact with the nasal mucosa.

[0005] Temperature-sensitive gels are a new type of drug dosage form that has emerged in recent years. They can undergo phase transition with changes in environmental temperature, and their minimum common solubility temperature is close to body temperature. The gel changes into a semi-solid gel at body temperature, prolonging the residence time in the drug administration site and achieving a sustained-release effect. Temperature-sensitive gels also have good permeability, swelling, viscoelasticity, water absorption, transparency, and biocompatibility.

[0006] The Chinese patent document with the publication number CN111388411A discloses a temperature-sensitive in-situ gel for relieving rhinitis and a preparation method thereof. The temperature-sensitive in-situ gel contains ephedrine hydrochloride, furacilin, poloxamer 407, poloxamer 188, an adhesion agent, an osmotic pressure regulator, a preservative, and the rest is water. After administration, the temperature-sensitive in-situ gel can immediately undergo phase transition at the administration site to form a semi-solid gel preparation from a liquid state, has good bioadhesion, can prolong the residence time of the drug in the nasal mucosa, and improve the bioavailability. However, the temperature-sensitive gel prepared by using poloxamer 407 as the gel material has the disadvantage of low adhesion.

[0007] The Chinese patent document with the publication number CN112121004A discloses a taurine nasal spray, a preparation method and application thereof. The taurine nasal spray contains the following components: 1-7% taurine, 15-40% temperature-sensitive in-situ gel material, and water. The application of taurine in the nasal spray together with the temperature-sensitive in-situ gel material prolongs the residence time of the drug in the nasal cavity and shows good therapeutic effect on allergic rhinitis.

[0008] However, it is difficult to achieve the co-delivery of two antiallergic drugs with large difference in solubility in the prior art, and it is difficult to exert the synergistic effect between the drugs.

[0009] In addition, through the query of the drug database of the State Food and Drug Administration, there are very few types of existing nasal sprays. The main drugs of the nasal sprays are hormones and decongestants. Hormone drugs are not suitable for long-term use due to the known toxic and side effects. Long-term use of nasal decongestants can cause rebound eye congestion, nasal congestion and edema, drug-induced rhinitis, etc. Therefore, it is necessary to find a drug that can effectively treat allergic rhinitis without the above-mentioned toxic and side effects to prepare a temperature-sensitive gel preparation for nasal use. SUMMARY

[0010] The present application provides a astragaloside IV-gallic acid conjugate obtained by esterification reaction of astragaloside IV and gallic acid. The astragaloside IV-gallic acid conjugate has better solubility in the temperature-sensitive gel system than astragaloside IV, and can realize the co-delivery of astragaloside IV and gallic acid in space and time, and facilitate the synergistic antiallergic effect of the two drugs.

[0011] The specific technical solutions adopted are as follows:

[0012] A astragaloside IV-gallic acid conjugate obtained by esterification reaction of astragaloside IV and gallic acid.

[0013] Specifically, the preparation method of the astragaloside IV-gallic acid conjugate comprises:

[0014] S01 Astragaloside IV and gallic acid are dissolved in a first organic solvent, and then dicyclohexyl carbodiimide and 4-dimethylaminopyridine are added as catalysts for stirring reaction;

[0015] S02 A second organic solvent is added to the system after the reaction of step S01, and then the obtained precipitate is washed and dried to obtain the Astragaloside IV-gallic acid conjugate.

[0016] Astragaloside IV (AST) has anti-inflammatory, anti-fibrosis, immunoregulatory and other pharmacological effects, and can intervene in multiple processes in the pathogenesis of inflammation, but Astragaloside IV is slightly soluble in water and has poor water solubility, which affects the exertion of drug efficacy; gallic acid (GA) is a natural polyphenolic compound with simple structure and good anti-allergic properties, and has good water solubility; the Astragaloside IV-gallic acid conjugate is obtained through esterification of the hydroxyl group in the Astragaloside IV molecule and the carboxyl group in the gallic acid molecule, which can improve the solubility of Astragaloside IV in the temperature-sensitive gel system, and can realize the simultaneous delivery of the two drugs in space and time, so as to facilitate the synergistic anti-allergic effect of the two drugs. The Astragaloside IV-gallic acid conjugate has amphiphilicity, which may lead to spontaneous aggregation of the conjugate to form particles in an aqueous environment, thereby exerting a certain drug release effect and being more conducive to the exertion of anti-allergic effect.

[0017] Preferably, in step S01, Astragaloside IV and gallic acid are reacted at a molar ratio of 1:0.9-1.1, and the catalyst is added in an amount of 2.5%-4.0% of the total amount of Astragaloside IV and gallic acid; the molar ratio of dicyclohexyl carbodiimide to 4-dimethylaminopyridine is 1:1-1.5.

[0018] Preferably, in step S01, the stirring reaction is carried out at a temperature of 45-55℃ for 12-18h.

[0019] Preferably, the first organic solvent is anhydrous N,N-dimethylformamide, and the second organic solvent is anhydrous diethyl ether; in step S02, the volume ratio of the amount of anhydrous diethyl ether to the amount of N,N-dimethylformamide is 10-15:1.

[0020] Preferably, in order to completely analyze the precipitate, the standing time is ≥1h.

[0021] The present application also provides a nasal temperature-sensitive gel which can be used for treating allergic rhinitis and contains the Astragaloside IV-gallic acid conjugate; specifically, the nasal temperature-sensitive gel contains the following components in the following weight percentages: Astragaloside IV-gallic acid conjugate 1%-1.5%, temperature-sensitive gel material 15-21.5%, and water.

[0022] Preferably, the temperature-sensitive gel material is selected from poloxamer 407, or a mixture of poloxamer 407 and thiolated poloxamer 407; the thiolated poloxamer 407 is obtained by thiolation modification of poloxamer 407 (both ends of -OH of poloxamer 407 are thiolated to -SH).

[0023] Further preferably, the temperature-sensitive gel material is a mixture of poloxamer 407 and thiolated poloxamer 407, and the mass ratio of poloxamer 407 to thiolated poloxamer 407 is 20:1-3. The addition of thiolated poloxamer 407 can improve the nasal mucosa adhesion of the nasal temperature-sensitive gel product.

[0024] The preparation method of the thiolated poloxamer 407 comprises:

[0025] S11 poloxamer 407 is added to water, dissolved thoroughly, then thiourea is added and mixed, followed by the addition of catalyst dilute hydrochloric acid and triethylamine, mixed, heated at 65-75℃ for 90-120min;

[0026] S12 methanol is added to the system after step S11, followed by washing, rotary evaporation and freeze-drying to obtain the thiolated poloxamer 407.

[0027] The application also provides a preparation method of the nasal temperature-sensitive gel, comprising:

[0028] S21 astragaloside IV-gallic acid conjugate is dissolved in water, and the pH is adjusted to 5.5-7.5;

[0029] S22 the aqueous solution of the temperature-sensitive gel material is mixed with the astragaloside IV-gallic acid conjugate solution prepared in step S21, and the nasal temperature-sensitive gel is obtained after standing.

[0030] The nasal temperature-sensitive gel is administered in the form of nasal spray, which is a free-flowing liquid at room temperature 25℃, and changes from liquid to gel at a temperature of 30-35℃.

[0031] Compared with the prior art, the application has the following beneficial effects:

[0032] (1) The astragaloside IV and gallic acid are combined together by chemical reaction in the application to obtain astragaloside IV-gallic acid conjugate, which can improve the solubility of astragaloside IV in the temperature-sensitive gel system, and realize the simultaneous delivery of the two drugs in space-time, so as to overcome the problem that anti-allergic drugs with large solubility difference are difficult to be delivered together.

[0033] (2) The prepared nasal temperature-sensitive gel is a free-flowing liquid at room temperature of about 25 DEG C, and becomes a solid-like gel after being adsorbed on the nasal mucosa, can prolong the release time of the drug, has good nasal mucosa adhesion, and prolongs the residence time of the drug in the nasal cavity. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 The figure is a nuclear magnetic resonance hydrogen spectrum of astragaloside, gallic acid and astragaloside-gallic acid combination.

[0035] Figure 2 The figure is an infrared spectrum of astragaloside, gallic acid and astragaloside-gallic acid combination.

[0036] Figure 3 The figure is a nuclear magnetic resonance hydrogen spectrum of thiolated poloxamer 407.

[0037] Figure 4 The figure is an infrared spectrum of poloxamer 407, thiourea and thiolated poloxamer 407.

[0038] Figure 5 The figure is an optical morphology of the nasal temperature-sensitive gel before and after gelation, wherein A is before gelation, and B is after gelation.

[0039] Figure 6 The figure is a gelation time statistical graph of the nasal temperature-sensitive gel at 33 DEG C and 35 DEG C.

[0040] Figure 7 The figure is a scanning electron microscope graph of the nasal temperature-sensitive gel, wherein A and B are scanning electron microscope graphs of the nasal temperature-sensitive gel without adding thiolated poloxamer 407 at different magnifications, and C and D are scanning electron microscope graphs of the nasal temperature-sensitive gel with adding thiolated poloxamer 407 at different magnifications.

[0041] Figure 8 The figure is a nasal mucosa adhesion force determination result of the nasal temperature-sensitive gel.

[0042] Figure 9 The figure is a nasal mucosa residence time determination result of the nasal temperature-sensitive gel. DETAILED DESCRIPTION

[0043] The application will be further illustrated below in combination with the embodiments and the drawings. It should be understood that the embodiments are only used for illustrating the application, and are not used for limiting the scope of the application.

[0044] Example 1 Synthesis of astragaloside-gallic acid combination

[0045] Accurately weigh 250 mg of astragaloside IV and 55 mg of gallic acid, dissolve them in 8 mL of anhydrous N,N-dimethylformamide, add 6 mg of dicyclohexylcarbodiimide and 5 mg of 4-dimethylaminopyridine, and stir at 45°C for 12 hours. Then, add 80 mL of anhydrous ether to the reaction mixture, let it stand for 1 hour, filter the precipitate, wash it, and rotary evaporate to obtain the astragaloside IV-gallic acid conjugate.

[0046] Example 2 Structural confirmation of astragaloside IV-gallic acid conjugate

[0047] 10 mg of astragaloside IV, gallic acid, and the astragaloside IV-gallic acid conjugate of Example 1 were weighed, dissolved in 0.6 mL of deuterated dimethyl sulfoxide, and then detected by nuclear magnetic resonance 1H spectrum to obtain a nuclear magnetic resonance 1H spectrum, as shown in FIG. Figure 1 The chemical shifts of hydrogen in astragaloside IV are all less than 6, while the chemical shifts of hydrogen in gallic acid are mainly greater than 7. The H NMR spectrum of the astragaloside IV-gallic acid conjugate shows the H spectral characteristics of both astragaloside IV and gallic acid. The characteristic hydrogen proton of the aromatic ring at δ7.76 indicates that the product structure contains a benzene ring. The results show that the astragaloside IV-gallic acid conjugate was successfully synthesized.

[0048] Weigh 20 mg of astragaloside IV, gallic acid, and astragaloside IV-gallic acid conjugate, respectively, and perform infrared detection on them to obtain the Fourier infrared spectrum ( Figure 2 Comparing the infrared spectrum of astragaloside IV-gallic acid conjugate and astragaloside IV, the infrared spectrum of astragaloside IV-gallic acid conjugate contains 1627, 1576 cm -1 The characteristic absorption peaks of the aromatic ring core structure indicate that the product contains a benzene ring structure. Combined with the results of H NMR and IR spectra, it is shown that the astragaloside-gallic acid conjugate was successfully synthesized.

[0049] Example 3 Determination of the solubility of astragaloside IV-gallic acid conjugate in water

[0050] Weigh sufficient amounts of astragaloside IV and the astragaloside IV-gallic acid conjugate of Example 1 into a 250 mL beaker, and add 100 mL of distilled water to dissolve. Stir continuously at 100 r / min at 25°C, and continuously add the sample to be tested during the stirring process until undissolved sample powder precipitates in the beaker and the dissolution reaches equilibrium. After standing still, take the upper suspension, centrifuge it at 12000 rpm for 10 min, take the supernatant and filter it through a 0.45 μm microporous membrane, and detect the drug concentration with an ultraviolet spectrophotometer. The measurement results show that the saturated solubility of astragaloside IV in water is 34.44 mg / 100 mL, and the molar concentration is 4.4×10 -4mol / L, and the molar concentration of the Astragaloside-IV-Gallic Acid conjugate was 3.2 x 10 -3 mol / L. Compared with Astragaloside-IV, the saturated solubility of the Astragaloside-IV-Gallic Acid conjugate in water increased by 7.27 times.

[0051] Example 4 Synthesis and structural confirmation of thiolated poloxamer 407

[0052] The thiolation reaction process of poloxamer 407 was carried out under the condition of hydrochloric acid as catalyst, and thiourea as nucleophile. The intermediate product was generated by the nucleophilic reaction of thiourea with hydrochloric acid, and the thiolated poloxamer 407 was obtained by treating the intermediate product with base. Specifically, 2.00 g of poloxamer 407 was precisely weighed and added to 100 mL of ultrapure water, and stirred to dissolve by a magnetic stirrer. Then 4.00 g of excess thiourea was added and ultrasonically dissolved. After adding 0.3 mL of dilute hydrochloric acid (4 mol / L), 4.67 g of triethylamine was added, and after stirring and mixing, it was heated in a 70°C water bath for 90 min. After the reaction was completed, 5 mL of methanol was added, and a certain amount of dilute hydrochloric acid and deionized water was repeatedly washed. After rotary evaporation at 80°C for 50 min until no obvious odor was detected, it was transferred to a culture dish and freeze-dried for 24 h to obtain thiolated poloxamer 407.

[0053] An appropriate amount of product was dissolved in 0.6 mL of deuterated dimethyl sulfoxide and loaded into an NMR tube, and the proton nuclear magnetic resonance spectrum was scanned, and the results are shown in Figure 3 ; another appropriate amount of product was ground with potassium bromide, and the Fourier infrared spectrum was scanned after tabletting, and the results are shown in Figure 4 .

[0054] From the above results and Figure 3 , it can be seen that there is a large hydrogen atom absorption peak near δ 1.0 ppm, indicating that there are many methylene groups in the sample molecules, which are attributed to poloxamer 407; there is a hydrogen atom absorption peak near δ 1.2 ppm, which is attributed to -SH; there is a hydrogen atom absorption peak near δ 3.4 ppm, which is attributed to the oxymethylene and oxymethyl of poloxamer 407.

[0055] As can be seen from Figure 4 , thiolated poloxamer 407 has two strong peaks at 731 cm -1 and 633 cm -1 , thiourea has two strong peaks at 730 cm -1 and 630 cm -1 , and poloxamer 407 has no peaks at 720-570 cm -1 , and the infrared results show that the product contains mercaptan. Poloxamer 407 has a peak at 3463 cm -1The stretching vibration peak of -OH in the raw material was observed, but not in the product, indicating that the hydroxyl group of poloxamer 407 was replaced by the mercapto group.

[0056] The characteristic peaks of poloxamer 407 and mercaptan appeared in the comprehensive nuclear magnetic resonance hydrogen spectrum and infrared spectrum, proving that the two ends of poloxamer 407 were successfully connected with mercapto groups.

[0057] Preparation of a nose-friendly temperature-sensitive gel

[0058] 1) Four portions of temperature-sensitive gel materials (poloxamer 407, or a mixture of poloxamer 407 and mercapto-poloxamer 407, each weighing 9.5 g, wherein the mass ratio of poloxamer 407 to mercapto-poloxamer 407 is 20:0, 20:1, 20:2, and 20:3, respectively) were accurately weighed, and 0.75 g of astragaloside IV-gallic acid conjugate prepared in Example 1 was accurately weighed and reserved.

[0059] 2) The astragaloside IV-gallic acid conjugate was added to a 30 mL centrifuge tube, and an appropriate amount of distilled water was added to make it a liquid. The pH value was adjusted to 5.5-7.5 with 1 mol / L NaOH solution.

[0060] 3) The temperature-sensitive gel material was added to a 50 mL centrifuge tube in portions and alternately with an appropriate amount of distilled water, and then the astragaloside IV-gallic acid conjugate solution was added. After mixing well, it was placed in a 4°C refrigerator for cold storage. When there were no particles, distilled water was added to 50 mL, and then it was placed in a 4°C refrigerator for 24 hours or more to obtain four kinds of nose-friendly temperature-sensitive gels containing astragaloside IV-gallic acid conjugate.

[0061] A representative picture of the nose-friendly temperature-sensitive gel is shown as A and B in Figure 5 , which is a transparent liquid at room temperature and turns into a semi-solid gel at 33-35°C, and does not slide when inverted.

[0062] Determination of the gelation temperature and time of a nose-friendly temperature-sensitive gel

[0063] The temperature-sensitive gel is usually a liquid with good flowability at room temperature, and it is difficult to adhere to the bottom of the test tube when the test tube is inverted. When the temperature rises to a certain value, it becomes a semi-solid state with poor flowability, and it can adhere to the bottom of the test tube when the test tube is inverted. A thermometer was inserted into a water bath, and the position of the thermometer was about 2 cm below the liquid surface. The temperature of the water bath was adjusted to 25°C, and 1.5 mL of the nose-friendly temperature-sensitive gel prepared in Example 5 was measured and transferred into a 2 mL centrifuge tube, and then placed in the water bath. Every 5 seconds or so, the centrifuge tube was taken out and turned over 180° to see if the temperature-sensitive gel changed from a liquid to a semi-solid. Every 2 minutes, the temperature was increased by 1°C, and the lowest temperature at which each sample changed to a semi-solid state and the time required were recorded.

[0064] The temperature of the nasal cavity of allergic rhinitis patients is usually between 33℃ and 35℃. In order to better investigate the phase transition effect of the temperature-sensitive gel when delivered nasally, the time required for each sample to change from a liquid to a semi-solid gel at 33℃ and 35℃ was measured. The gelling temperatures of the four temperature-sensitive gels prepared in Example 5 were 27℃, 27℃, 28.5℃ and 30℃, respectively, all of which were higher than room temperature 25℃ and lower than the temperature of the nasal mucosa. Therefore, the prepared temperature-sensitive gels are not easy to change to a gel state at room temperature, which facilitates administration and helps to control the dosage of the drug; and can change from a liquid to a gel state when sprayed on the nasal mucosa, which facilitates better adsorption on the nasal mucosa and prolongs the residence time of the drug.

[0065] The time required for the four liquid preparations to change from a liquid to a gel state at 33℃ and 35℃ is shown in Table 2. The addition of thiolated poloxamer 407 appropriately prolongs the time required for gelling. The temperature-sensitive gel before gelling has strong fluidity and is easy to flow to the throat, causing drug loss, so the gelling time should be as short as possible, and the proportion of thiolated poloxamer 407 should not be too high. Figure 6

[0066] Example 7 Morphological characteristics of the nasal temperature-sensitive gel

[0067] The nasal temperature-sensitive gel after forming a gel state was freeze-dried, and after freeze-drying was completed, scanning electron microscopy was performed. The freeze-dried gel was cut into appropriate size slices, a carbon adhesive label was pasted on an aluminum sheet, a drop of liquid glue was dripped on it, the freeze-dried gel slice was placed on the glue, and then the plate was gold-plated for 10 min under the MC1000 ion sputtering instrument, and finally it was placed under a scanning electron microscope for photography to obtain a scanning electron microscope image of the sample. The results are shown in Figs. 5A-5D. When the temperature-sensitive gel material is all poloxamer 407, the surface is relatively smooth, and when an appropriate amount of thiolated poloxamer 407 is added (poloxamer 407:thiolated poloxamer 407 = 20:3), the surface becomes rough. The scanning electron microscope image suggests that the change in the surface morphology of the temperature-sensitive gel is related to the change in its adhesion, and the addition of thiolated poloxamer 407 can improve its adhesion. Figure 7

[0068] Example 8 pH determination of the nasal temperature-sensitive gel

[0069] An appropriate amount of each of the four nasal temperature-sensitive gels prepared in Example 5 at room temperature was taken, the proportions of poloxamer 407 and thiolated poloxamer 407 were 20:0, 20:1, 20:2 and 20:3, respectively, and they were placed in beakers. The pH of each sample was measured with a pH meter, and the results are shown in Table 1. The pH of the prepared nasal temperature-sensitive gels was between 5.5 and 7.5, which meets the pH requirements of nasal preparations.

[0070] Table 1 Results of pH determination ​​

[0071]

[0072] Example 9: Adhesion Test of Nasal Thermosensitive Gel

[0073] The four thermosensitive nasal gels prepared in Example 5 were divided into four groups. The ratios of poloxamer 407 to thiolated poloxamer 407 in the thermosensitive nasal gels for Groups 1, 2, 3, and 4 were 20:0, 20:1, 20:2, and 20:3, respectively. A 2 mL sample was taken from each group and heated in a water bath until it became a semisolid. The adhesion strength of the samples was measured using a texture analyzer. During the test, a probe applied a force of 0.0098 N to the sample and then automatically retracted. The force required to remove the probe from the gel was used to assess the sample's adhesion.

[0074] The results are as follows Figure 8 As shown, when the ratio of poloxamer 407 to thiolated poloxamer 407 is 20:0, the adhesion force of the thermosensitive nasal gel is approximately 0.09 N; when the ratio of poloxamer 407 to thiolated poloxamer 407 is 20:1, the adhesion force of the thermosensitive nasal gel is approximately 0.19 N; when the ratio of poloxamer 407 to thiolated poloxamer 407 is 20:2, the adhesion force of the thermosensitive nasal gel is approximately 0.20 N; and when the ratio of thiolated poloxamer 407 is 20:3, the adhesion force of the thermosensitive nasal gel is approximately 0.33 N. This indicates that the greater the proportion of thiolated poloxamer 407, the greater the adhesion force of the thermosensitive gel.

[0075] Example 10 Determination of Nasal Mucosal Retention Time of Nasal Thermosensitive Gel

[0076] Twelve SD rats were divided into three groups. Group A was given a nasal thermosensitive gel containing 0.5% isatin solution (poloxamer 407: thiolated poloxamer 407 = 20:0), Group B was given a nasal thermosensitive gel containing 0.5% isatin solution (poloxamer 407: thiolated poloxamer 407 = 20:3), and Group C was given a 0.5% isatin saline solution as a control. After the rats were anesthetized with sodium pentobarbital solution, 10 μL of thermosensitive gel containing 0.5% isatin solution or saline was drawn with a pipette and dripped into the nasal cavity of the rats according to the groups. Every 3 minutes after administration, the drug retention in the nose of the rats was observed, and the retention time of the thermosensitive gel in the nasal mucosa was used to evaluate the retention time of the thermosensitive gel. The results are shown in Figure 2. Figure 9 It was shown that when an appropriate amount of thiolated poloxamer 407 was added to the thermosensitive gel material, the retention time of the prepared thermosensitive gel in the nasal mucosa was increased.

[0077] The above embodiments of the present application are described in detail, it should be understood that the above described are only specific embodiments of the present application, and are not intended to limit the present application, any modification, supplement or similar way of substitution made within the principle range of the present application, should be included in the protection scope of the present application.

Claims

1. A nose-friendly temperature-sensitive gel, characterized in that, The nasal temperature-sensitive gel comprises the following components by weight percentage: astragaloside IV-gallic acid conjugate 1-1.5%, temperature-sensitive gel material 15-21.5%, and water; The temperature-sensitive gel material is a mixture of poloxamer 407 and thiolated poloxamer 407, and the mass ratio of poloxamer 407 to thiolated poloxamer 407 is 20:1-3; The astragaloside IV-gallic acid conjugate is obtained by esterification of astragaloside IV and gallic acid.

2. The nose- sensitive gel according to claim 1, characterized in that, The preparation method of the astragaloside IV-gallic acid conjugate comprises: S01 dissolving astragaloside IV and gallic acid in a first organic solvent, adding dicyclohexyl carbodiimide and 4-dimethylaminopyridine as catalysts, and stirring to react; S02 adding a second organic solvent to the system after the reaction of step S01, and standing, washing and drying the obtained precipitate to obtain the astragaloside IV-gallic acid conjugate.

3. The nose- sensitive gel of claim 2, wherein, In step S01, the astragaloside IV and gallic acid are reacted at a molar ratio of 1:0.9-1.1; the catalyst is added in an amount of 2.5%-4.0% of the total amount of astragaloside IV and gallic acid; and the molar ratio of dicyclohexyl carbodiimide to 4-dimethylaminopyridine is 1:1-1.

5.

4. The nose -sensitive gel according to claim 2, characterized in that, In step S01, the stirring temperature is 45-55°C, and the stirring time is 12-18h.

5. The nose-specific temperature-sensitive gel of claim 2, wherein, The first organic solvent is anhydrous N,N-dimethylformamide, and the second organic solvent is anhydrous ether; in step S02, the volume ratio of the amount of anhydrous ether to the amount of N,N-dimethylformamide is 10-15:

1.

6. The method for preparing the thermosensitive nasal gel according to claim 1, wherein: Comprising: S21 dissolving the astragaloside IV-gallic acid conjugate in water and adjusting the pH to 5.5-7.5; S22 mixing the aqueous solution of the temperature-sensitive gel material with the astragaloside IV-gallic acid conjugate solution prepared in S21, and standing to obtain the nasal temperature-sensitive gel.

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