A nasal preparation, its preparation method and application

Abstract

This invention belongs to the field of traditional Chinese medicine technology, specifically relating to a nasal preparation, its preparation method, and its application. This invention uses ferulic acid, an effector component obtained through extraction and purification of Ligusticum chuanxiong, as the active pharmaceutical ingredient, combined with pharmaceutical excipients, to prepare a traditional Chinese medicine nasal preparation for intranasal administration. Animal experiments have demonstrated that the nasal preparation provided by this invention has significant relieving and therapeutic effects on tension-type headaches. Furthermore, as a topical liquid preparation, the preparation is stable, non-irritating to the administration site, and exhibits good compliance, showing promising clinical application prospects. It represents a new option for nasal preparations in the field of traditional Chinese medicine for treating tension-type headaches.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a nasal preparation, its preparation method, and its application. Background Technology

[0002] Headache is one of the most common clinical symptoms. It generally refers to pain localized to the upper half of the head, including the area above the line connecting the eyebrows, the upper edge of the auricle, and the external occipital protuberance. The causes of headaches are numerous, including neuralgia, intracranial infections, intracranial space-occupying lesions, cerebrovascular diseases, and extracranial head and facial diseases. In 2018, the Headache Classification Committee of the International Headache Society (IHS) published the third edition of the International Classification of Headache Disorders (ICHD-3), which defines and diagnoses various types of headaches. In ICHD-3, primary headaches are divided into four categories: migraine, tension-type headache, trigeminal autonomic headache, and other primary headaches.

[0003] Tension-type headache (TTH), the most common type of primary headache, has become a significant global public health problem. Characterized by bilateral mild to moderate pressure headaches, often accompanied by neck and shoulder muscle tension, it significantly impacts patients' work efficiency and quality of life. Epidemiological surveys show a global prevalence of tension-type headache as high as 26%. Data from the Global Burden of Disease 2021 (GBD 2021) further confirms that tension-type headache ranks high among neurological disease burdens, and its incidence, prevalence, and age-standardized daily average (DALY) rate are projected to continue rising from 2022 to 2035, indicating a continuously increasing disease burden, particularly among women. Therefore, it is necessary to implement preventative and treatment measures for tension-type headache and establish a comprehensive prevention and control system. Emphasis should be placed on strengthening intervention strategies targeting women to effectively reduce the incidence of tension-type headache in my country and alleviate the disease burden.

[0004] The pathogenesis of tension headaches is not fully understood. Clinically, non-narcotic analgesics (such as ibuprofen and other nonsteroidal anti-inflammatory drugs) are often used, but these only relieve pain and have significant side effects. Therefore, further research and development of drugs to treat or relieve tension headaches remains essential. Ferulic acid is a natural phenolic compound that is easily metabolized in the body, has high safety, and possesses multiple biological activities, making it an important subject for research and application of natural functional components. However, ferulic acid has poor stability in solution, and currently, solid formulations are the primary focus, with limited research and development of liquid formulations.

[0005] In view of this, the present invention is hereby proposed. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a nasal preparation, its preparation method, and its application. This preparation has a significant effect in treating or relieving tension headaches, and its effects are stable with no side effects.

[0007] Specifically, the technical solution of the present invention is as follows: In a first aspect, the present invention provides a nasal preparation comprising a pharmaceutically active ingredient and excipients; wherein the pharmaceutically active ingredient is a ferulic acid effect component extracted from Ligusticum chuanxiong, and the excipients include polysorbate and disodium edetate.

[0008] The nasal formulation of this invention is a liquid formulation. On the one hand, this liquid formulation facilitates the rapid onset of action of the active pharmaceutical ingredient in the treatment or relief of tension headaches; on the other hand, this liquid formulation helps reduce corresponding adverse reactions while treating or relieving tension headaches. Furthermore, this invention adds polysorbate and disodium edetate to the liquid formulation of the ferulic acid effector, which significantly improves the stability of the ferulic acid effector in the formulation.

[0009] The ferulic acid effector component of this invention is extracted from Ligusticum chuanxiong and exhibits significant advantages in relieving and treating tension-type headaches. In a more specific embodiment, the ferulic acid effector component of this invention is prepared from crude Ligusticum chuanxiong through steps such as alcohol extraction, elution, and concentration. Preferably, the amount of crude Ligusticum chuanxiong corresponding to 1 mL of the ferulic acid effector component is 2-5 g, more preferably 4 g.

[0010] In a more specific embodiment, the preparation method of the ferulic acid effect component of the present invention is as follows: Ligusticum chuanxiong is first extracted twice by reflux with 6-10 times the amount of 70% ethanol, each time for 1-2 hours; the extract is filtered, the filtrates are combined, and concentrated under reduced pressure until there is no alcohol odor; the concentration is further increased to 0.25g crude drug / mL; the extract is adsorbed through a macroporous adsorption resin, eluted with 50% ethanol, and the eluent is collected; the ethanol is recovered under reduced pressure until there is no alcohol odor; the concentration is further increased to 3-5g crude drug / mL to obtain the ferulic acid effect component.

[0011] The excipients of the nasal formulation of the present invention include polysorbate and disodium edetate. Polysorbate is used as a solubilizer, increasing the solubility of insoluble substances; preferably, it is polysorbate 80 and / or polysorbate 20.

[0012] In this invention, the ferulic acid effector component in the nasal formulation is present at a content of 50 vol%-75 vol%, preferably 55 vol%-70 vol%, more preferably 60-65 vol%, and even more preferably 62.5 vol%. The polysorbate in the nasal formulation is present at a content of 0.5 vol%-3.0 vol%, more preferably 1.0 vol%-2.0 vol%, and even more preferably 1.5 vol%. The disodium edetate in the nasal formulation is present at a content of 0.05-0.5 g / L, more preferably 0.06-0.1 g / L. The nasal formulation with the above-mentioned proportions exhibits better stability.

[0013] In this invention, the osmolality of the nasal preparation is preferably 280-310 mOsmol / kg. The pH value of the nasal preparation is preferably 4.0-6.0, more preferably 4.5-5.5, and even more preferably 5.0. The above-mentioned osmolality range and pH range help reduce irritation to the nasal area during use and also contribute to the stability of the nasal preparation itself. The pH adjuster is preferably one or more of sodium hydroxide, hydrochloric acid, sodium citrate, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium bicarbonate; the osmolality adjuster is preferably sodium chloride and / or glucose, more preferably sodium chloride.

[0014] In this invention, the nasal preparation further contains an absorption enhancer, preferably a borneol HP-β-cyclodextrin inclusion complex. This invention preferably controls the mass ratio of the absorption enhancer to the osmotic pressure regulator. Specifically, taking sodium chloride as an osmotic pressure regulator, in this invention, the mass ratio of the borneol HP-β-cyclodextrin inclusion complex to sodium chloride is preferably 1.5-2.5:0.5-0.7, more preferably 2.0:0.6. This preferred ratio helps increase the residence time of the nasal preparation on the mucosal surface, increases the moisturizing sensation at the application site, and improves comfort; it also prevents excessive viscosity that could cause discomfort or irritation; simultaneously, it helps improve the long-term stability of the nasal preparation.

[0015] In this invention, the nasal preparation preferably further contains an antioxidant. The antioxidant is preferably one or more selected from sodium bisulfite, sodium metabisulfite, ascorbic acid, and L-cysteine. Specifically, the concentration of sodium bisulfite in the nasal preparation is 1-2 g / L, the concentration of sodium metabisulfite in the nasal preparation is 1-2 g / L, the concentration of vitamin C in the nasal preparation is 0.5-2 g / L, and the concentration of cysteine ​​hydrochloride in the nasal preparation is 0.2-0.5 g / L. More preferably, the antioxidant is sodium bisulfite, which has a significant synergistic effect with disodium edetate, further improving the stability of ferulic acid.

[0016] In this invention, the nasal preparation preferably further contains an antibacterial agent. The antibacterial agent is preferably one or more selected from potassium sorbate, sodium benzoate, benzalkonium chloride, ethylparaben, and methylparaben. Specifically, the content of potassium sorbate in the nasal preparation is <3 g / L, the content of sodium benzoate in the nasal preparation is <3 g / L, the content of benzalkonium chloride in the nasal preparation is 0.01-0.02 g / L, the content of ethylparaben in the nasal preparation is 0.1-2 g / L, and the content of methylparaben in the nasal preparation is 0.1-2 g / L.

[0017] In a more specific and preferred embodiment, the antibacterial agent used in this invention is potassium sorbate, and the antioxidant used is sodium bisulfite. This selection ensures the product is sterile and antioxidant while minimizing irritation to the nasal mucosa, thereby avoiding nasal mucosal irritation or discomfort caused by the antibacterial agent and antioxidant.

[0018] Secondly, the present invention provides a method for preparing the aforementioned nasal preparation, the method comprising the step of dissolving the pharmaceutically active ingredient and excipients in purified water.

[0019] In a more specific embodiment, the preparation method of the present invention includes: taking the prescribed amount of ferulic acid effect component, diluting and stirring with purified water, slowly adding the prescribed amount of absorption promoter, stirring to dissolve, then slowly adding the prescribed amount of polysorbate while stirring, then adding disodium edetate and other excipients, stirring to dissolve, adjusting the pH value, adding purified water to the final concentration, stirring, filtering, and filling to obtain the final product.

[0020] The preparation method provided by this invention facilitates better dispersion of pharmaceutical active ingredients, improves product stability, and helps reduce irritation to mucous membranes.

[0021] Thirdly, the present invention also provides the use of the nasal preparation, or the nasal preparation prepared by the preparation method, in the production of a medicament for the prevention or treatment of tension headaches.

[0022] Preferably, the drug is a nasal spray (such as a nasal spray). As a topical liquid preparation, the nasal spray has no side effects and is effective in treating or relieving tension headaches; it is stable and has a long shelf life.

[0023] Beneficial effects:

[0024] This invention provides a nasal preparation, its preparation method, and its application. The nasal preparation comprises a pharmaceutically active ingredient and excipients; the pharmaceutically active ingredient is a ferulic acid effector obtained from Ligusticum chuanxiong, with a content of 50 vol%-75 vol% in the nasal preparation; the excipients include polysorbate and disodium edetate. The nasal preparation provided by this invention, as a topical liquid preparation, is stable, has a long shelf life, and provides significant relief and treatment for tension headaches. It is also non-irritating to the administration site and exhibits good compliance. Detailed Implementation

[0025] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0026] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0027] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "specific implementation," or "some specific implementations," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0028] The endpoints and any values ​​of the ranges disclosed in this specification are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0029] In the embodiments provided in this specification, unless specific techniques or conditions are specified, the techniques or conditions described in the literature in this field, or the product instructions, shall be followed. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased from legitimate channels.

[0030] Example 1

[0031] This embodiment provides a nasal spray, the specific formulation of which is shown in Table 1.

[0032] Table 1

[0033] This embodiment provides a method for preparing the above-mentioned nasal spray, the steps of which are as follows:

[0034] (1) Preparation of ferulic acid effect component: Take 250g of Ligusticum chuanxiong, add 8 times the amount of 70% ethanol, soak for 1h, extract twice under reflux conditions, 1.5h each time, filter, combine the filtrates, concentrate under reduced pressure below 70℃ until there is no alcohol taste, continue to concentrate to 1000mL, adsorb through 250g of D101 macroporous adsorption resin, elute with purified water until the eluent is colorless, discard the water eluent; then elute with 4BV 50% ethanol, collect the eluent, recover the ethanol under reduced pressure at 70℃ until there is no alcohol taste, continue to concentrate to 62.5ml, and the ferulic acid effect component is obtained for use.

[0035] (2) Preparation of borneol HP-β-cyclodextrin inclusion complex: Take 5.0g of borneol and add it to 50mL of ethanol and stir well. Take another 40g of HP-β-cyclodextrin and dissolve it in 200mL of ethanol and stir well. Under magnetic stirring, slowly add the borneol ethanol solution. After the addition is complete, continue stirring for 10min to mix evenly. Concentrate under reduced pressure to dryness, take it out, wash it 3 times with ethyl acetate, evaporate the ethyl acetate at room temperature, dry it under vacuum at 40℃, grind it, and pass it through an 80-mesh sieve to obtain the borneol HP-β-cyclodextrin inclusion complex for later use.

[0036] (3) Preparation of nasal spray: Take the prescribed amount of ferulic acid effect component, add purified water to 80 mL, stir well, slowly add the prescribed amount of borneol HP-β-cyclodextrin inclusion complex, stir to dissolve, then slowly add the prescribed amount of polysorbate 80 while stirring, then add sodium bisulfite, potassium sorbate, disodium edetate and sodium chloride in sequence, stir well to dissolve, adjust the pH value to 5.0 with citric acid-sodium citrate, add purified water to 100 mL, stir well, filter, fill and seal to obtain nasal spray.

[0037] Examples 2-6

[0038] Examples 2-6 provide nasal sprays with different formulations, as shown in Table 2.

[0039] Table 2

[0040] The preparation methods of the nasal sprays described in Examples 2-6 are the same as those in Example 1.

[0041] Examples 7-11

[0042] Examples 7-11 provide nasal sprays with different formulations, as shown in Table 3.

[0043] Table 3

[0044] The preparation methods of the nasal sprays described in Examples 7-11 are the same as those in Example 1.

[0045] Example 12

[0046] This embodiment provides a nasal spray, the specific formulation of which is shown in Table 4.

[0047] Table 4

[0048] Example 13

[0049] This embodiment provides a nasal spray, the specific formulation of which is shown in Table 5.

[0050] Table 5

[0051] Example 14 This embodiment provides a nasal spray, the specific formulation of which is shown in Table 6.

[0052] Table 6

[0053] Comparative Example 1

[0054] This comparative example provides a nasal spray, the specific formulation of which is shown in Table 7.

[0055] Table 7

[0056] Comparative Example 2

[0057] This comparative example provides a nasal spray, the specific formulation of which is shown in Table 8.

[0058] Table 8

[0059] Experimental Example 1

[0060] This experimental example uses the nasal spray (number CX01) prepared in Example 1 for efficacy testing.

[0061] After 7 days of acclimatization, the rats were randomly divided into a normal control group (hereinafter referred to as the normal group), a model group, a CX01 nasal spray group (1 / 2ED group 92.5μL / kg, hereinafter referred to as the CX01 low-dose group), a CX01 nasal spray group (ED group 185μL / kg, hereinafter referred to as the CX01 medium-dose group), and a CX01 nasal spray group (2ED group, hereinafter referred to as the CX01 370μL / kg high-dose group). A rat model of tension-type headache was established by local injection of ATP into the bilateral semispinalis muscles of the neck. The test drug CX01 nasal spray was administered via intranasal drops three times a day to both nostrils for 7 consecutive days. Pain thresholds in the rat paws and orbits were measured using Vonfrey fibers. The levels of serum inflammatory mediators TNF-α, TGF-β, and IL-6, as well as the levels of serum and brain tissue vasoactive mediators 5-HT, NO, and iNOS, and the level of pain mediator SP were detected to investigate the therapeutic effect of CX01 nasal spray on tension-type headache induced by local injection of ATP into the bilateral semispinalis muscles of the neck in rats.

[0062] Behavioral indicators: The pain threshold levels of rat paws and periorbital skin were measured using von-Frey pain-measuring fiber guidewires.

[0063] Serum marker detection: ELISA kits are used to detect the levels of TGF-β, TNF-α, IL-6, 5-HT, SP, NO and NOS in serum.

[0064] Brain tissue homogenate index detection: ELISA kits were used to detect the levels of 5-HT, SP, NO and NOS in brain tissue homogenates.

[0065] The experimental results are as follows:

[0066] Table 9. Effects of nasal spray on plantar pain threshold in rats (Mean±SD, n=10)

[0067] Note: Compared with the normal group * P <0.05, ** P <0.01, *** P <0.001, **** P <0.0001; compared with the model group, # P <0.05, ## P <0.01,### P <0.001, #### P <0.0001.

[0068] Compared with the normal group, the plantar pain threshold of rats in the model group was reduced during the test, and the difference was statistically significant. P The value is less than 0.0001, indicating that the model was successfully built.

[0069] Compared with the model group, after the first modeling and drug administration: the plantar pain threshold of rats in the CX01-low-dose group was increased, but there was no statistically significant difference. P> 0.05); The plantar pain threshold of rats in the CX01 medium and high dose groups increased, and the differences were statistically significant. P< 0.01, P< 0.01). Seven days after administration, the plantar pain threshold of each rat was measured at 1 h and 2 h after modeling and administration. The results showed that the plantar pain threshold of rats in the CX01-low-dose group increased at 1 h and 2 h, and the differences were statistically significant. P< 0.01, P< 0.01); In the CX01-medium dose group, the plantar pain threshold of rats increased at 1h and 2h, and both differences were highly statistically significant ( P< 0.0001, P< 0.0001); In the CX01 high-dose group, the plantar pain threshold of rats increased at 1h and 2h, and both differences were statistically significant. P< 0.0001, P< 0.0001).

[0070] Table 10 Effect of nasal spray on orbital pain threshold in rats (Mean±SD, n=10)

[0071] Note: Compared with the normal group **** P <0.0001; compared with the model group, # P <0.05, ## P <0.01, #### P <0.0001.

[0072] Compared with the normal group, the orbital pain threshold of rats in the model group was reduced at the time of testing, and the difference was statistically significant. P The value is less than 0.0001, indicating that the model was successfully built.

[0073] Compared with the model group, after the first modeling and drug administration, the orbital pain threshold of each rat was measured 2 hours later. The orbital pain threshold of rats in the CX01 low, medium and high dose groups was increased, but there was no statistically significant difference. P> 0.05, P> 0.05, P> 0.05). Seven days after administration, the orbital pain threshold of each rat was measured at 1 hour and 2 hours after modeling and administration. The results showed that the orbital pain threshold of the CX01-low-dose group was increased at both 1 hour and 2 hours, and the differences were statistically significant. P <0.01, P <0.0001); the orbital pain threshold of rats in the CX01-medium dose group increased at 1h and 2h, and both differences were statistically significant. P< 0.0001, P< 0.0001); The orbital pain threshold of rats in the CX01 high-dose group increased at 1h and 2h, and both differences were highly statistically significant ( P< 0.0001, P< 0.0001).

[0074] Table 11 Effects of nasal spray on serum levels of inflammatory mediators TNF-α, TGF-β, and IL-6 in rats (Mean ± SD, n = 10)

[0075] Note: Compared with the normal group **** P <0.0001; compared with the model group, ### P <0.001, #### P <0.0001.

[0076] Compared with the normal group, the serum TNF-α, TGF-β, and IL-6 levels in the model group rats were significantly elevated. P <0.0001). Compared with the model group, after 7 days of administration, the serum TNF-α levels in rats in the low, medium, and high dose CX01 groups were decreased, and all showed highly statistically significant differences. P <0.0001, P <0.0001, P <0.0001). Serum TGF-β levels in rats in the low, medium, and high dose groups of CX01 were decreased, and all showed highly statistically significant differences. P <0.001, P <0.0001, P <0.0001), serum IL-6 levels in rats in the low, medium, and high dose groups of CX01 decreased, and all differences were statistically significant.P <0.001, P <0.0001, P <0.0001).

[0077] Table 12 Effects of nasal spray on serum levels of vasoactive mediators 5-HT, NO, and iNOS in rats (Mean ± SD, n = 10)

[0078] Note: Compared with the normal group **** P <0.0001; compared with the model group, # P <0.05, ## P <0.01, ### P <0.001, #### P <0.0001.

[0079] Compared with the normal group, the serum levels of 5-HT, NO, and iNOS in the model group rats were significantly elevated (P<0.0001).

[0080] Compared with the model group, after 7 days of administration, the serum 5-HT levels in rats in the low, medium, and high dose groups of CX01 decreased, and all differences were statistically significant. P <0.001, P <0.0001, P <0.0001). Serum NO levels in rats in the low, medium, and high dose groups of CX01 decreased, and all differences were statistically significant. P <0.01, P <0.01, P <0.001). Serum iNOS levels were decreased in the CX01-low-dose group of rats, with a statistically significant difference ( P< 0.05); Serum iNOS levels in rats in the CX01 medium and high dose groups were decreased, and the differences were statistically significant. P< 0.0001, P< 0.0001).

[0081] Table 13 Effects of CX nasal spray on the levels of vasoactive mediators 5-HT, NO, and iNOS in rat brain tissue (Mean±SD, n=10)

[0082] Note: Compared with the normal group **** P <0.0001; compared with the model group,## P <0.01, ### P <0.001, #### P <0.0001.

[0083] Compared with the normal group, the levels of 5-HT, NO, and iNOS in the brain tissue of rats in the model group were significantly increased. P <0.0001).

[0084] Compared with the model group, after 7 days of administration, the levels of 5-HT in the brain tissue of rats in the low, medium, and high dose groups of CX01 were decreased, and all differences were statistically significant (P<0.001, P<0.0001, P<0.0001). The levels of NO in the brain tissue of rats in the low, medium, and high dose groups of CX01 were also decreased, and all differences were statistically significant (P<0.001, P<0.0001). P< 0.01, P< 0.001, P< 0.0001). The iNOS level in the brain tissue of rats in the low-dose CX01 group was reduced, but there was no statistically significant difference (P>0.05); the iNOS level in the brain tissue of rats in the medium- and high-dose CX01 groups was reduced, and the differences were extremely statistically significant (P<0.01, P<0.001).

[0085] Table 14 Effects of CX nasal spray on serum and brain tissue levels of the pain mediator SP in rats (Mean±SD, n=10)

[0086] Note: Compared with the normal group **** P <0.0001; compared with the model group, ## P <0.01, #### P <0.0001.

[0087] Effect on serum SP levels: Compared with the normal group, the serum SP levels in the model group rats were significantly elevated. P <0.0001). Compared with the model group, after 7 days of administration, the serum SP levels of rats in the CX01-low, medium, and high dose groups were decreased, and all showed highly statistically significant differences. P <0.01, P <0.0001, P <0.0001).

[0088] Effects on SP levels in brain tissue: Compared with the normal group, the SP levels in the brain tissue of rats in the model group were significantly increased. P <0.0001). Compared with the model group, after 7 days of administration, the SP level in the brain tissue of rats in the low, medium, and high dose CX01 groups decreased, and all differences were statistically significant. P <0.0001, P <0.0001, P <0.0001).

[0089] The above experimental results show that the nasal spray prepared in Example 1 has a significant therapeutic effect on tension headaches. Repeating the above efficacy experiments with nasal sprays obtained in other examples yielded essentially the same conclusions, all demonstrating a significant therapeutic effect on tension headaches.

[0090] Experiment Example 2 This experiment used the nasal spray (model number CX01) prepared in Example 1 for animal irritation testing. Test drug: CX01 nasal spray; Experimental animals: 9 healthy adult New Zealand rabbits, ordinary grade, weighing 2.5-2.9 kg, 5 females and 4 males.

[0091] The specific experimental method is as follows: Nine rabbits were randomly divided into three groups of three based on their weight: a drug administration group, an excipient group, and a negative control group. The drug administration group received CX01 nasal spray, the excipient group received excipient solution, and the negative control group received physiological saline. The dosage was 185 μL / kg, administered for 7 consecutive days.

[0092] Post-administration observation: No changes were observed in the animals' overall condition (including respiratory, circulatory, and central nervous system) or local irritation symptoms (including asthma, cough, vomiting, and suffocation). Animals were sacrificed 24 hours after the last administration, and nasal mucosa was dissected and examined for congestion, edema, secretions around the nostrils, crusting, etc. Nasal mucosal irritation response scores and irritation intensity were evaluated according to Tables 15 and 16.

[0093] Table 15 Nasal Mucosal Irritation Response Scores

[0094] Table 16 Evaluation of Nasal Mucosal Irritation Intensity

[0095] Evaluation results: Macroscopic observation of the nasal mucosa tissue of rabbits in the CX01 nasal spray administration group, excipient group and control group showed no lesions such as congestion, edema, perinasal secretions, or crusting. The average irritation intensity score was 0 points for all groups, and the evaluation was non-irritating.

[0096] Experimental Example 3 This experiment uses the nasal spray prepared in Example 1 to conduct accelerated stability and long-term stability experiments. The results are shown in Tables 17-20.

[0097] Table 17 Results of accelerated stability test (40℃±2℃, RH75%±5%)

[0098] Table 18 Results of long-term stability test (25℃±2℃, RH60%±5%)

[0099] Table 19 Results of accelerated stability test (comparative example) (40℃±2℃, RH75%±5%)

[0100] Table 20 Results of long-term stability test (comparative example) (25℃±2℃, RH60%±5%)

[0101] The above experimental results show that the liquid formulations of each embodiment are more stable and have a longer shelf life than the comparative example; among all embodiments, the liquid formulation of Example 1 has the best stability.

[0102] The embodiments described above are merely illustrative of several implementations of the present invention, designed to facilitate a detailed understanding of the technical solutions of the present invention. However, they should not be construed as limiting the scope of patent protection. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. A nasal preparation, characterized in that, It includes a pharmaceutically active ingredient and excipients; the pharmaceutically active ingredient is a ferulic acid effect component extracted from Ligusticum chuanxiong, and its content in the nasal preparation is 50 vol%-75 vol%; the excipients include a solubilizer and a stabilizer, wherein the solubilizer is polysorbate and the stabilizer is disodium edetate.

2. The nasal preparation according to claim 1, characterized in that, The content of disodium edetate in the nasal preparation is 0.05-0.5 g / L; the content of polysorbate in the nasal preparation is 0.5 vol%-3.0 vol.

3. The nasal preparation according to claim 1, characterized in that, The pH value of the nasal preparation is 4.0-6.0, preferably 4.5-5.

5.

4. The nasal preparation according to claim 1, characterized in that, The osmolar concentration of the nasal preparation is 280-310 mOsm / L.

5. The nasal preparation according to claim 1, characterized in that, The excipients also include an absorption enhancer, which is a borneol-HP-β-cyclodextrin inclusion complex, and its concentration in the nasal preparation is 10-40 g / L.

6. The nasal preparation according to claim 1, characterized in that, The excipients also include antioxidants, which are selected from one or more of sodium bisulfite, sodium metabisulfite, vitamin C, and cysteine ​​hydrochloride; preferably sodium bisulfite.

7. The nasal preparation according to claim 1, characterized in that, The excipients also include an osmotic pressure regulator, which is selected from sodium chloride and / or glucose, preferably sodium chloride.

8. The nasal preparation according to any one of claims 1-7, characterized in that, The amount of raw Ligusticum chuanxiong corresponding to each 1 mL of the ferulic acid effect component is 2-5 g.

9. A method for preparing the nasal preparation according to any one of claims 1-7, characterized in that, The preparation method includes the step of dissolving the pharmaceutical active ingredient and excipients in purified water.

10. The use of the nasal preparation according to any one of claims 1-7, or the nasal preparation prepared by the method according to claim 9, in the production of a medicament for the prevention or treatment of tension headaches.

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