A high drug-loading breviscapine hydrophilic self-gel and its preparation method

Abstract

The present invention provides a highly drug-loaded breviscapine hydrophilic self-gel and a preparation method thereof. The formula uses a hydrophilic solvent system as a dispersion medium, overcoming the drawback of using toxic organic solvents as the dispersion medium. Breviscapine is both an active ingredient and a gelling factor, eliminating the need for additional gelling materials. The preparation method is simple and efficient, and the resulting gel has a high drug loading, excellent percutaneous permeability, good stability, and high safety. The formula is simple and the preparation method is easy, facilitating industrial production and application.

Description

Technical Field

[0001] [1] The present invention relates to the field of pharmaceutical technology, and particularly relates to a hydrophilic self-gel of breviscapine with high drug loading, and a process for preparing the breviscapine gel. Background Art

[0002] [2] Breviscapine is extracted and isolated from the dried whole herb of Erigeron breviscapus (Vant.) Hand.-Mazz. (also known as Erigeron breviscapus), mainly composed of scutellarin, and belongs to flavonoid active ingredients. Breviscapine has a wide range of pharmacological effects such as anti-inflammatory, antioxidant, improving cerebral and cardiac ischemia, anti-fibrosis, anti-tumor, etc. Clinically, it is mainly used for cardiovascular and cerebrovascular diseases, and related products are mainly administered orally or by injection; when used externally, it can antibacterial, promote wound healing, inhibit scar formation, prevent pigment deposition, etc., but there is currently a lack of corresponding breviscapine preparations for skin or mucosa.

[0003] [3] Breviscapine is almost insoluble in water (<1mg / ml), and its solubility is even lower in most organic solvents (such as dichloromethane, ethyl acetate, etc.), and its solubility in organic solvents such as methanol and ethanol is less than 5mg / ml, which brings great inconvenience to its handling and application.

[0004] [4] Gels are a commonly used dosage form, which are easy to prepare, convenient to use, and have strong compatibility. When used externally, they can be applied by smearing, sticking, filling, etc., and are used for human skin, mucosa, body cavities and other parts. Among them, hydrogels use water as the main dispersion medium, which has a wide range of applicable drugs, simple and efficient preparation methods, and convenient carrying and use. The prescription generally selects hydrophilic polymer materials such as polyvinyl alcohol, carbomer, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polysaccharides, etc. as the gel, and in addition, pH regulators, moisturizers, bacteriostatic agents, transdermal absorption promoters, etc. are also needed to improve its performance. Hydrogels are usually prepared by a dispersion process. First, the required gel materials are dispersed in an appropriate amount of water, and after they are fully swollen to form a gel, drugs and other components of the prescription are added and mixed evenly. The drugs in the hydrogel system may be highly dispersed in a dissolved, emulsion droplet or suspension particle state, but there are potential unstable phenomena such as aggregation and growth, and stratification of the emulsion droplet or particle state.

[0005] [5]The prior art "Effect of Different Transdermal Absorption Promoters on Transdermal Absorption of Breviscapine Gel" (Fang Rui et al., Chinese Traditional Patent Medicine, 34(06): 1174-1176, 2012) discloses a breviscapine-loaded gel and its preparation method, using carbomer as the gel material, adding glycerol as a humectant, azone as a transdermal absorption promoter, methylparaben as an antibacterial agent, etc. The prior art "Preparation and Quality Evaluation of Propranolol Hydrochloride Gel" (Zhang Zhihua et al., Central South Pharmacy, 10(05): 345-349, 2012) discloses a hydrogel loaded with propranolol hydrochloride and its preparation method, using 2.5% hydroxypropyl methylcellulose as the gel matrix, prepared by the direct swelling method, and adding glycerol as a humectant, Tween 60 as a solubilizer, geraniol as a transdermal absorption promoter and fragrance, ethylparaben as an antibacterial agent, etc. The prior art "Preparation and Properties of Polyvinyl Alcohol Composite Hydrogel External Membrane" (Feng Yan et al., Progress in Modern Biomedicine, 14(02): 244-246, 2014) discloses an external membrane based on composite hydrogel and its preparation method, using polyvinyl alcohol, dextran, sodium carboxymethyl cellulose as hydrogel materials, using water as a solvent, and preparing a hydrogel by a heating dispersion process. All of the above granulation technologies need to add a large amount of specific gel materials to form a gel, and use water as a dispersion medium to form a hydrogel by swelling and dispersion, and need to add a variety of additives.

[0006] [6]In the previous research of the inventor's team, it was unexpectedly found that breviscapine has the ability of self-gelation in organic solvents, and based on this, a self-gel of breviscapine in an organic solvent system was developed (see patent application number 2023103971849 "A Breviscapine Organic Gel and Its Preparation Method"). However, a large amount of organic solvents with toxic and side effects, such as dichloromethane, need to be used in the above system, which is difficult to be directly and safely applied to clinical practice. Moreover, the inventor found that if water is directly used as a poor solvent, due to the large polarity of water molecules, it interferes with the cross-linking of hydroxyl groups of breviscapine and cannot form a gel. [7] It can be seen that there is a need in the prior art to study a breviscapine hydrophilic self-gel with high drug loading and high safety. Based on a large number of studies, the present invention uses the drug itself as the gel material, uses a specific hydrophilic solvent system as the dispersion medium, and prepares a gel by a conventional anti-solvent precipitation method; the obtained gel has a high drug loading, good stability, does not require other additives, and can quickly penetrate and absorb through the skin. Summary of the Invention

[0007] [8]The purpose of the present invention is to provide a breviscapine hydrophilic self-gel with high drug loading and high safety. Directly using the active ingredient breviscapine as the gel material and using a specific hydrophilic solvent system as the dispersion medium. It solves the technical problem that only organic solvents with large toxic and side effects can be used as the dispersion medium in the previous research, and the application range is narrow.

[0008] [9]Another object of the present invention is to provide a preparation method of the above-mentioned breviscapine hydrophilic self-gel with high drug loading and high safety, and the preparation method is simple and controllable.

[0009]

[10] The inventors of the present invention found in previous studies that breviscapine has the ability of self-gelation. Without limitation, the inventors believe that part of the reason for this self-gelation may be due to the molecular interactions between breviscapine molecules and between breviscapine molecules and the solvent. That is to say, after breviscapine is fully dissolved in a good solvent and then uniformly dispersed in a poor solvent, as the solubility decreases, breviscapine precipitates out, and the molecules of breviscapine cross-link with each other through groups such as hydroxyl groups to form a three-dimensional network structure, and the structure voids are filled with the solvent, thus forming a gel containing only breviscapine as a component except for the solvent.

[0010]

[11] Hydrophilic gels usually do not require the use of highly toxic organic solvents and have high clinical safety. Water is generally considered to be a poor solvent for breviscapine. However, the inventors found in the study that if water is directly used as the poor solvent, due to the large polarity of water molecules, it interferes with the cross-linking of hydroxyl groups of breviscapine and cannot form a breviscapine hydrophilic self-gel. Therefore, it is difficult for those skilled in the art to develop a breviscapine hydrophilic self-gel.

[0011]

[12] The inventor team unexpectedly found a specific hydrophilic solvent system through a large number of experiments, which can ensure the formation of a breviscapine hydrophilic self-gel, thus completing the present invention. The principle may be related to the change in the polarity of the aqueous solution caused by the specific hydrophilic solvent system and the interaction between specific molecules in the specific hydrophilic solvent system and breviscapine molecules. It should be noted that the specific hydrophilic solvent system does not contain gel materials.

[0012]

[13] Specifically, the present invention provides the following technical solutions:

[0013] A breviscapine hydrophilic self-gel, characterized in that it is composed of only breviscapine and a hydrophilic solvent, without other gel materials. Breviscapine serves as both an active ingredient and a gel factor at the same time. The hydrophilic solvent is basically a poor solvent for breviscapine, and the poor solvent is a solvent system obtained by mixing one or more of glycerol, pentanediol, and hexanediol with water.

[0014]

[14] Preferably, the poor solvent is a solvent system obtained by mixing glycerol with water. Particularly preferably, the glycerol and water are mixed in a volume ratio of 5:95 - 95:5. Further preferably, the glycerol and water are mixed in a volume ratio of 30:70 - 70:30.

[0015]

[15] In this text, "the hydrophilic solvent is substantially a poor solvent for breviscapine" means that the hydrophilic solvent as a whole exhibits the properties of a poor solvent, that is, breviscapine is insoluble or poorly soluble in the hydrophilic solvent. For example, although a good solvent is used in the process of preparing the hydrophilic self-gel of breviscapine, the good solvent can be removed in the final product; it can be understood that the good solvent can also not be removed, but since the relative amount of the good solvent is small and the poor solvent dominates in the whole hydrophilic solvent system, the hydrophilic solvent as a whole exhibits the properties of a poor solvent.

[0016]

[16] The content of breviscapine in the hydrophilic self-gel will have a certain impact on the properties of the gel. In order to obtain a product with better gel properties, the inventor believes that the content of breviscapine should be ≥1%. Preferably, the content of breviscapine should be ≥2%, and most preferably, the content of breviscapine should be ≥4%.

[0017]

[17] Without removing the good solvent, the hydrophilic solvent is composed of a good solvent and a poor solvent for breviscapine, wherein the amount of the good solvent can make the breviscapine contained in the gel fully dissolve therein; the amount of the poor solvent can make the solution of the good solvent dissolved with breviscapine fully dispersed.

[0018]

[18] Correspondingly, the good solvent can also be removed, and the removal method is a conventional method in the art, such as evaporation, dialysis, extraction, displacement and other methods.

[0019]

[19] Preferably, the good solvent is dimethyl sulfoxide, N-methylpyrrolidone, N,N-diethylacetamide, N,N-dimethylformamide or a mixed solvent thereof.

[0020]

[20] Particularly preferably, the good solvent is dimethyl sulfoxide.

[0021]

[21] Preferably, the weight ratio of the good solvent to the poor solvent is 1:39 - 1:4.

[0022]

[22] Preferably, the gel does not flow down when inverted in a container, or the ratio of the viscosity of the system to the viscosity of the used solvent is not less than 10, or the storage modulus G' of the system is higher than the loss modulus G" in rheological detection.

[0023]

[23] The present invention also provides a preparation method of the breviscapine hydrophilic self-gel as described above, which is characterized in that: it is prepared by an anti-solvent precipitation method, wherein the anti-solvent precipitation method is to weigh an appropriate amount of breviscapine raw material drug, add a good solvent to make it completely dissolve, and then mix it evenly with a poor solvent, and remove or not remove the good solvent to obtain the gel.

[0024]

[24] More preferably, during the preparation of the gel by the anti-solvent precipitation method, auxiliary means such as ultrasonic and high-speed shearing are used to make the good solvent and the poor solvent mix evenly.

[0025]

[25] Preferably, the auxiliary means is ultrasound.

[0026]

[26] The method for preparing the breviscapine molecular gel provided by the present invention is simple, low in price and good in reproducibility.

[0027]

[27] In summary, the inventors surprisingly found through research that by using an appropriate hydrophilic solvent system, a breviscapine molecular gel can be prepared, which can form a high-strength gel preparation by itself without adding a gel material, and its percutaneous penetration performance is also improved. And no excipients and special equipment are required in the process of preparing the gel, which saves costs and is convenient for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028]

[28] Figure 1 It is the appearance diagram and microscopic diagram of the breviscapine hydrogel in Examples 1, 2, 3 and the breviscapine suspension in Comparative Example 1.

[0029]

[29] Figure 2 It is the rheological viscosity curve (A) and temperature scanning curve (C) of the breviscapine hydrogel in Examples 1, 2, 3 and the breviscapine suspension in Comparative Example 1 and the frequency scanning curve of Example 3 (B).

[0030]

[30] Figure 3 It is the appearance diagram of the breviscapine hydrogel in Examples 4-13.

[0031]

[31] Figure 4 It is the appearance diagram of the breviscapine suspension in Comparative Examples 2-17.

[0032]

[32] Figure 5 It is the in vitro transdermal curve and related parameters of the breviscapine hydrogel in Example 3 and the breviscapine suspension in Comparative Example 2.

[0033]

[33] Next, the technical solutions obtained in the embodiments of the present invention will be clearly and completely described in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0034]

[34] Example 1: Weigh the breviscapine raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; mix the above solution (1 part) with a mixed solvent of glycerol and water (volume ratio 7:3, 39 parts) under ultrasonic conditions (ice bath, 800W, 3min) to obtain the breviscapine hydrogel (see Appendix Figure 1 b).

[0035]

[35] Example 2: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; mix the above solution (1 part) with a mixed solvent of glycerol and water (volume ratio 7:3, 19 parts) under ultrasonic conditions (ice bath, 800 W, 3 min) to obtain scutellarin hydrogel (see Appendix Figure 1 c).

[0036]

[36] Example 3: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; mix the above solution (1 part) with a mixed solvent of glycerol and water (volume ratio 7:3, 9 parts) under ultrasonic conditions (ice bath, 800 W, 3 min) to obtain scutellarin hydrogel (see Appendix Figure 1 d).

[0037]

[37] Example 4: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; mix the above solution (1 part) with a mixed solvent of glycerol and water (volume ratio 1:1, 9 parts) under ultrasonic conditions (ice bath, 800 W, 2 min) to obtain scutellarin hydrogel (see Appendix Figure 3 a).

[0038]

[38] Example 5: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; mix the above solution (1 part) with a mixed solvent of glycerol and water (volume ratio 3:7, 9 parts) under ultrasonic conditions (ice bath, 800 W, 2 min) to obtain scutellarin hydrogel (see Appendix Figure 3 b).

[0039]

[39] Example 6: Weigh the scutellarin raw material and add an appropriate amount of N,N - diethylacetamide to completely dissolve it to form a drug solution with a concentration of 10%; mix the above solution (1 part) with a mixed solvent of glycerol and water (volume ratio 1:9, 1.5 parts) under ultrasonic conditions (ice bath, 800 W, 2 min) to obtain scutellarin hydrogel (see Appendix Figure 3 c).

[0040]

[40] Example 7: Weigh the scutellarin raw material and add an appropriate amount of N,N - dimethylformamide to completely dissolve it to form a drug solution with a concentration of 10%; mix the above solution (1 part) with a mixed solvent of glycerol and water (volume ratio 0.5:9.5, 1.5 parts) under ultrasonic conditions (ice bath, 800 W, 2 min) to obtain scutellarin hydrogel (see Appendix Figure 3 d).

[0041]

[41] Example 8: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; mix the above solution (1 part) with a mixed solvent of pentanediol and water (volume ratio 1:4, 5.5 parts) under ultrasonic conditions (ice bath, 600 W, 6 min) to obtain scutellarin hydrogel (see Appendix Figure 3 e).

[0042]

[42] Example 9: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; mix the above solution (1 part) with a mixed solvent of pentanediol and water (volume ratio 1:1, 5.5 parts) under ultrasonic conditions (ice bath, 400 W, 8 min) to obtain scutellarin hydrogel (see Appendix Figure 3 f).

[0043]

[43] Example 10: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 10%; mix the above solution (1 part) with a mixed solvent of hexanediol and water (volume ratio 1:4, 5 parts) under ultrasonic conditions (ice bath, 600 W, 8 min) to obtain scutellarin hydrogel (see Appendix Figure 3 g).

[0044]

[44] Example 11: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; mix the above solution (1 part) with a mixed solvent of hexanediol and water (volume ratio 1:1, 4 parts) under ultrasonic conditions (ice bath, 800 W, 6 min) to obtain scutellarin hydrogel (see Appendix Figure 3 h).

[0045]

[45] Example 12: Weigh the scutellarin raw material and add an appropriate amount of N-methylpyrrolidone to completely dissolve it to form a drug solution with a concentration of 40%; mix the above solution (1 part) with a mixed solvent of glycerol and water (volume ratio 7:3, 9 parts) under ultrasonic conditions (ice bath, 800 W, 6 min) to obtain scutellarin hydrogel (see Appendix Figure 3 i).

[0046]

[46] Example 13: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; mix the above solution (1 part) with a mixed solvent of glycerol and water (volume ratio 7:3, 9 parts) under high-speed shearing conditions (10000 rpm, 1 min) to obtain scutellarin hydrogel (see Appendix Figure 3 j).

[0047]

[47] Example 14: Take 5 mg of breviscapine raw material medicine, add a small amount of solvent, vortex and mix well, and observe the state of the system; if the drug is not completely dissolved, continue to add a small amount of solvent; repeat this process until the drug is completely dissolved and the system is clear. Record the amount of solvent required and calculate the approximate solubility of breviscapine in this solvent.

[0048] Breviscapine is readily soluble in dimethyl sulfoxide, pyridine and N-methylpyrrolidone, and also has a relatively high solubility in N,N-diethylacetamide and N,N-dimethylformamide, all of which can be used as potential good solvents.

[0049]

[49] Combined with the examples and comparative examples, it is found that dimethyl sulfoxide has a wide adaptability, can form a gel with breviscapine in most cases, and has low toxicity, is safer, and can be miscible with the vast majority of solvents. Therefore, it is used as the preferred good solvent.

[0050]

[50] Example 15: Characterization of the properties of breviscapine hydrogel

[0051] Take appropriate amounts of the breviscapine hydrogels obtained in Example 1 (1%), Example 2 (2%), and Example 3 (4%) and the breviscapine suspension in Comparative Example 1 (0.5%), add them to the rheometer sample stage, and measure the viscosity in the range of shear rate from 0.01 / s to 0.1 / s and measure the change of the modulus of the gel with temperature in the oscillation mode, so as to obtain the transition temperature of the system from the gel state to the solution state; and conduct a frequency sweep test on Example 3 (4%) under the fixed condition of selecting a strain of 0.01% in the viscoelastic region. The results are shown in Figure 2 。

[51] Figure 2 A shows that in the low-speed shear range, the viscosity of Example 3 (4%) is higher; Figure 2 B shows that the storage modulus (G’) of the product obtained in Example 3 is greater than the loss modulus (G”), and as the angular frequency increases, the former increases faster, showing a semi-solid substance, that is, gel formation. Figure 3 c shows that in the temperature range of 25 - 120 °C, the transition temperature of the 4% hydrogel from the gel state to the solution state is 120 °C, and the ratio of its storage modulus (G’) to the loss modulus (G”) is larger than that of the 2% and 1% hydrogels, indicating that this system has better stability to temperature.

[0052]

[52] Example 16: It can be seen from Example 3 that the self-gelling concentration of breviscapine in the glycerol-water (7:3) mixed system is 4%, and its system viscosity is 2035.80 Pa·s at a shear rate of 0.01 / s; the breviscapine concentration in Example 2 is 2%, and its system viscosity is 517.90 Pa·s at a shear rate of 0.01 / s; thus, it can be seen that the 4% self-gel has better gel performance than the 2% self-gel; therefore, the more preferred concentration of breviscapine in the breviscapine self-gel is ≥4%.

[0053]

[53] Example 15: The in vitro transdermal performance of the hydrophilic self-gel of scutellarin obtained in Example 3 and the scutellarin suspension in Comparative Example 2 was measured. The Franz transdermal diffusion instrument was used, with the mouse back skin as the barrier and phosphate buffer (pH = 6.8) as the receiving medium. The drug concentration in the receiving solution was measured at the predetermined time point; the in vitro permeation curve was drawn, and the key parameters such as the permeation rate, cumulative permeation amount and intradermal retention amount were calculated. The results are shown in Figure 5 .

[0054]

[54] The results showed that the transdermal performance of breviscapine hydrogel was significantly better than that of the corresponding suspension. It was not only rapidly absorbed without a lag phase, but also had a 3.8-fold increase in the cumulative skin permeation within 12 hours and a 4.4-fold increase in the steady-state transdermal rate.

[0055]

[55] The present application also conducted the following experiment during the screening process, which is given here as a comparative example:

[0056] Comparative Example 1: Weigh the raw material of breviscapine and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) is fully mixed with a mixed solvent of glycerol and water (volume ratio 7:3, 79 parts) under ultrasonic conditions (ice bath, 800W, 2min) (see attached Figure 1 a).

[0057]

[56] Comparative Example 2: Breviscapine raw material and a mixed solvent of glycerol and water (volume ratio 7:3, 4% w / v) were weighed and thoroughly mixed under vortex conditions. The resulting mixed system failed to form a gel (see attached Figure 4 a).

[0058]

[57] Comparative Example 3: Breviscapine raw material was weighed and an appropriate amount of dimethyl sulfoxide was added to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was fully mixed with a mixed solvent of glycerol and water (volume ratio 0.1:9.9, 9 parts) under ultrasonic conditions (ice bath, 800W, 3min), and the resulting mixed system failed to form a gel (see attached Figure 4 b).

[0059]

[58] Comparative Example 4: Weigh the raw material of breviscapine and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was fully mixed with a mixed solvent of pentanediol and water (volume ratio 1:9, 9 parts) under ultrasonic conditions (ice bath, 600W, 2min), and the resulting mixed system failed to form a gel (see attached Figure 4 c).

[0060]

[59] Comparative Example 5: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was ultrasonically treated (ice bath, 400 W, 4 min) and mixed well with a mixed solvent of pentanediol and water (volume ratio 1:4, 9 parts), and the resulting mixed system failed to form a gel (see Appendix Figure 4 d).

[0061]

[60] Comparative Example 6: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was ultrasonically treated (ice bath, 600 W, 6 min) and mixed well with a mixed solvent of pentanediol and water (volume ratio 1:1, 9 parts), and the resulting mixed system failed to form a gel (see Appendix Figure 4 e).

[0062]

[61] Comparative Example 7: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was ultrasonically treated (ice bath, 600 W, 3 min) and mixed well with a mixed solvent of hexanediol and water (volume ratio 1:4, 5.5 parts), and the resulting mixed system failed to form a gel (see Appendix Figure 4 f).

[0063]

[62] Comparative Example 8: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was ultrasonically treated (ice bath, 800 W, 2 min) and mixed well with a mixed solvent of methanol and water (volume ratio 1:1, 5.5 parts), and the resulting mixed system failed to form a gel (see Appendix Figure 4 g).

[0064]

[63] Comparative Example 9: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was ultrasonically treated (ice bath, 200 W, 1 min) and mixed well with a mixed solvent of trifluoroacetic acid and water (volume ratio 1:1, 9 parts), and the resulting mixed system failed to form a gel (see Appendix Figure 4 h).

[0065]

[64] Comparative Example 10: Weigh the scutellarin raw material and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was ultrasonically treated (ice bath, 800 W, 5 min) and mixed well with a mixed solvent of 1,4-dioxane and water (volume ratio 1:1, 9 parts), and the resulting mixed system failed to form a gel (see Appendix Figure 4 i).

[0066]

[65] Comparative Example 11: Weigh the raw material of breviscapine and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was fully mixed with a mixed solvent of glycerol, ethanol and water (volume ratio 1:2:2, 9 parts) under ultrasonic conditions (ice bath, 800W, 5min), and the resulting mixed system failed to form a gel (see attached Figure 4 j).

[0067]

[66] Comparative Example 12: Breviscapine raw material was weighed and added with an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was fully mixed with a mixed solvent of PEG400 and water (volume ratio 1:1, 3 parts) under ultrasonic conditions (ice bath, 600W, 4min), and the resulting mixed system failed to form a gel (see attached Figure 4 k).

[0068]

[67] Comparative Example 13: Breviscapine raw material was weighed and added with an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was fully mixed with a mixed solvent of PEG400 and water (volume ratio 7:3, 9 parts) under ultrasonic conditions (ice bath, 600W, 4min), and the resulting mixed system failed to form a gel (see attached Figure 4 l).

[0069]

[68] Comparative Example 14: Weigh the raw material of breviscapine and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was fully mixed with a mixed solvent of ethanol and water (volume ratio 1:1, 4 parts) under ultrasonic conditions (ice bath, 600W, 4min), and the resulting mixed system failed to form a gel (see attached Figure 4 m).

[0070]

[69] Comparative Example 15: Weigh the raw material of breviscapine and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was fully mixed with a mixed solvent of acetonitrile and water (volume ratio 7:3, 9 parts) under ultrasonic conditions (ice bath, 400W, 2min), and the resulting mixed system failed to form a gel (see attached Figure 4 n).

[0071]

[70] Comparative Example 16: Weigh the raw material of breviscapine and add an appropriate amount of dimethyl sulfoxide to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was fully mixed with water (9 parts) under ultrasonic conditions (ice bath, 400W, 2min), and the resulting mixed system failed to form a gel (see attached Figure 4 o).

[0072]

[71] Comparative Example 17: Breviscapine raw material was weighed and an appropriate amount of pyridine was added to completely dissolve it to form a drug solution with a concentration of 40%; the above solution (1 part) was fully mixed with a mixed solvent of glycerol and water (volume ratio 7:3, 9 parts) under ultrasonic conditions (ice bath, 800W, 2min), and the resulting mixed system failed to form a gel (see attached Figure 4 p).

[0073]

[72] The above are only preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limiting the present invention. The protection scope of the present invention should be based on the scope defined by the claims. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the spirit and scope of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A breviscapine hydrophilic self-gel, which is characterized in that: It is only composed of breviscapine and a hydrophilic solvent, without other gel materials. Breviscapine serves as both the active ingredient and the gel factor at the same time; The hydrophilic solvent is composed of a good solvent and a poor solvent of breviscapine. The amount of the good solvent can make the breviscapine contained in the gel dissolve completely; the amount of the poor solvent can make the solution of the good solvent in which breviscapine is dissolved disperse fully; the weight ratio of the good solvent to the poor solvent is 1:39 - 1:4; The poor solvent is a solvent system obtained by mixing one of glycerol, pentanediol, and hexanediol with water; the volume ratio of glycerol to water is 5:95 - 95:5; the volume ratio of pentanediol and hexanediol to water is 1:1 or 1:4; The good solvent is dimethyl sulfoxide, N-methylpyrrolidone, N,N-diethylacetamide, N,N-dimethylformamide or a mixed solvent thereof; The preparation method is: prepared by the anti-solvent precipitation method. In the anti-solvent precipitation method, an appropriate amount of breviscapine raw material medicine is weighed, added with the good solvent to make it dissolve completely, and then mixed evenly with the poor solvent. Whether to remove the good solvent or not, the gel is obtained; During the preparation of the gel by the anti-solvent precipitation method, ultrasound or high-speed shearing is used to mix the good solvent and the poor solvent evenly.

2. The breviscapine hydrophilic self-gel according to claim 1, which is characterized in that: Calculated by the weight of the gel, the content of breviscapine is ≥1%.

3. The breviscapine hydrophilic self-gel according to any one of claims 1 - 2, which is characterized in that: The gel does not flow down when inverted in a container, or the ratio of the viscosity of the system to the viscosity of the solvent used is not less than 10, or the storage modulus G' of the system is higher than the loss modulus G" in rheological detection.

4. A preparation method of the breviscapine hydrophilic self-gel according to any one of claims 1 - 3, which is characterized in that: Prepared by the anti-solvent precipitation method. In the anti-solvent precipitation method, an appropriate amount of breviscapine raw material medicine is weighed, added with the good solvent to make it dissolve completely, and then mixed evenly with the poor solvent. Whether to remove the good solvent or not, the gel is obtained; during the preparation of the gel by the anti-solvent precipitation method, ultrasound or high-speed shearing is used to mix the good solvent and the poor solvent evenly.

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