Nasal spray containing aryl propionic acid compound as well as preparation method and application of nasal spray

Abstract

The invention relates to a nasal spray containing an aryl propionic acid compound as well as a preparation method and application of the nasal spray. The nasal spray is prepared from any one of the following raw materials: (1) pharmaceutically acceptable salt of the aryl propionic acid compound, an ionic strength regulator and water; and (2) an aryl propionic acid compound, alkali, an ionic strength regulator and water. The concentration of the aryl propionic acid compound in the nasal spray is 50 to 150 mg / mL; the ionic strength regulator is used for regulating the pH value of the nasal spray to 6.0-7.0 and regulating the osmotic pressure of the nasal spray to 300-1000 mOsm / kg. The nasal spray provided by the invention has the characteristics of quick response, good analgesic effect and high safety, and provides a non-opioid analgesic choice which is efficient, powerful and convenient to use for acute pain patients.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a nasal spray containing an arylpropionic acid compound and a preparation method and application thereof. BACKGROUND

[0002] Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used analgesic and anti-inflammatory drugs in clinical, and are widely used in postoperative pain, acute pain, trauma and chronic low back pain. Most of the currently marketed products will be administered by oral or injection. Traditional oral or injection NSAIDs are difficult to meet the needs of acute or breakthrough pain management due to slow onset or inconvenient operation. Therefore, the nasal spray with rapid onset has gradually attracted attention. As a non-invasive drug delivery method, nasal administration has the advantages of rapid onset, convenience, high compliance, no first-pass effect, less adverse reactions, mucosal immunity, etc. Many systemic drugs exist in the form of nasal spray, which are often used for the treatment of analgesics, migraine, osteoporosis and nausea.

[0003] As the only marketed NSAIDs nasal spray, ketorolac tromethamine nasal spray (Sprix ® ) is highly praised for its convenience and rapid onset, but its use is limited to no more than 5 days due to adverse reactions. The average physiological pH value of human nasal mucosa is 6.3, and the prescription pH value of ketorolac tromethamine nasal spray is 7.2, which has the risk of drug precipitation in the nasal mucosa. Other NSAIDs, such as diclofenac sodium, meloxicam, ibuprofen, celecoxib and flurbiprofen, are difficult to achieve the required concentration for onset due to low solubility in water, so the development of nasal spray is limited. Therefore, the development of a high-concentration, rapid-onset and strong analgesic NSAIDs nasal spray has become an important direction in this field.

[0004] Loxoprofen sodium is an arylpropionic acid non-steroidal anti-inflammatory drug developed by the First Sanwa Company of Japan, which has the potential to prepare a nasal spray due to its good water solubility. However, it is a prodrug itself, which needs to be metabolized by enzymes in the body to generate an active metabolite (2'S, 1'R, 2'S)-trans-hydroxy active metabolite to exert its effect, which will limit its onset speed in nasal local administration.

[0005] Patent CN111825547A discloses a salt of arylpropionic acid compound and its pharmaceutical use, which involves an injection solution containing the tromethamine salt of the active metabolite of loxoprofen sodium as the active ingredient. The prescription contains a main drug with a maximum concentration of 10 mg / mL, sodium chloride and water for injection, and the pH is adjusted to 7.4 with tromethamine solution to achieve the stability of the solution. Due to its high water solubility (> 250 mg / mL) and strong analgesic effect, it is a feasible development strategy.

[0006] However, when preparing high-concentration drug solution, it is found that as the concentration of the drug solution increases, the pH value of the drug solution also increases (more alkaline), and the osmotic pressure of the drug solution is greater. The average physiological pH value of human nasal mucosa is acidic, and the alkaline drug solution has the risk of precipitation in the nasal mucosa. In addition, high osmotic pressure solution can cause irritation to the nasal mucosa, and long-term or frequent use can cause mucosal damage, leading to symptoms such as bleeding, pain and increased secretion.

[0007] Therefore, it has become one of the technical problems to be solved to develop a nasal spray containing arylpropionic acid compounds, which can reasonably adjust the pH value and osmotic pressure while increasing the drug concentration, avoid nasal irritation, and improve the long-term stability of the preparation. SUMMARY

[0008] In view of the deficiencies of the prior art, the purpose of the present application is to provide a nasal spray containing arylpropionic acid compounds and a preparation method and application thereof. The nasal spray has the characteristics of high solubility, high stability, low irritation, rapid onset and good bioavailability, and has good application prospects in the treatment of acute or breakthrough pain and as preoperative anesthesia.

[0009] To achieve this purpose, the present application adopts the following technical solutions:

[0010] In a first aspect, the present application provides a nasal spray containing arylpropionic acid compounds, and the preparation raw materials of the nasal spray include any one of the following components:

[0011] (1) a pharmaceutically acceptable salt of arylpropionic acid compounds, an ionic strength regulator and water;

[0012] (2) arylpropionic acid compounds, a base, an ionic strength regulator and water.

[0013] The structure of the arylpropionic acid compound is shown in formula I;

[0014] Formula I;

[0015] In component (1), the concentration of the pharmaceutically acceptable salt of arylpropionic acid compounds in the nasal spray is 50-150 mg / mL, calculated as the free acid of arylpropionic acid compounds.

[0016] In component (2), the concentration of arylpropionic acid compounds in the nasal spray is 50-150 mg / mL.

[0017] The ionic strength regulator is used to adjust the pH value of the nasal spray to 6.0-7.0 and the osmotic pressure of the nasal spray to 300-1000 mOsm / kg.

[0018] Specific values ​​for the 50-150 mg / mL range can be selected from 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 105 mg / mL, 110 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, and 150 mg / mL. Specific values ​​for the 6.0-7.0 range can be selected from 6.0, 6.2, 6.4, 6.6, 6.8, and 7.0. Specific values ​​for the 300-1000 mOsm / kg range can be selected from 300 mOsm / kg, 400 mOsm / kg, 500 mOsm / kg, 600 mOsm / kg, and 600 mOsm / kg. mOsm / kg, 700 mOsm / kg, 800 mOsm / kg, 900 mOsm / kg, 1000 mOsm / kg, etc.

[0019] This invention provides a nasal spray with a concentration of 50-150 mg / mL of aryl propionic acid compounds. It maintains high stability and low irritation even at high drug concentrations, providing sufficient dosage to achieve the effective blood drug concentration with a limited single-dose volume (usually 50-150 μL).

[0020] This invention limits the pH value of aryl propionic acid compounds in nasal sprays to 6.0-7.0, fully taking into account the compatibility of nasal sprays with the physiological environment of the nasal cavity (close to 6.3).

[0021] The present invention limits the osmotic pressure of aryl propionic acid compounds in nasal sprays to 300-1000 mOsm / kg, taking into account that high concentrations of drugs themselves will result in high osmotic pressure, increasing irritation to the nasal cavity.

[0022] This invention adjusts the pH of high-concentration nasal sprays to 6.0-7.0 and the osmotic pressure to 300-1000 mOsm / kg by adding an ionic strength regulator, significantly reducing the local irritation of the nasal spray to the nasal mucosa. Simultaneously, the aforementioned ionic strength regulator, which regulates both pH and osmotic pressure, also ensures the long-term stability of high-concentration nasal sprays, preventing precipitation, improving biocompatibility, and achieving an optimal balance between minimizing irritation, protecting nasal mucosal function, and maintaining drug stability, thereby improving user tolerance and comfort.

[0023] Preferably, the pharmaceutically acceptable salt of the arylpropionic acid compound in component (1) comprises a sodium salt or a tromethamine salt of the arylpropionic acid compound, preferably a tromethamine salt of the arylpropionic acid compound.

[0024] The structure of the tromethamine salt of the arylpropionic acid compound is shown in Formula II.

[0025] Formula II.

[0026] The physical state of the pharmaceutically acceptable salt of the arylpropionic acid compound is a crystalline state or an amorphous state.

[0027] Preferably, the base in component (2) comprises tromethamine and / or sodium hydroxide.

[0028] Preferably, the molar ratio of the arylpropionic acid compound and the base in component (1) is 1:0.5-1:2, preferably 1:0.9-1:1.

[0029] Specific point values in 1:0.5-1:2 can be selected from 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc.

[0030] It should be noted that the tromethamine salt of the arylpropionic acid compound having the structure shown in Formula II is completely ionized into the acid ion of the compound having the structure shown in Formula I and the tromethamine cation after being dissolved in water. The compound having the structure shown in Formula II and the compound having the structure shown in Formula I + tromethamine dissolved in water have the same type of ions in the aqueous solution. Therefore, the prescription compositions of the above two preparation forms are within the protection scope and disclosure scope of the present application.

[0031] Preferably, the ionic strength adjusting agent comprises a pH adjusting agent.

[0032] Preferably, the pH adjusting agent comprises an acidic pH adjusting agent.

[0033] Further, the present application uses an acidic pH adjusting agent as an ionic strength adjusting agent to further lower the pH value of the arylpropionic acid compound aqueous solution, inhibit dissociation to reduce the osmotic pressure of the solution, thereby reducing the irritation of the nasal spray to the nasal mucosa, while exploring a suitable pH value range to maintain the stability of the nasal spray.

[0034] In addition, the tromethamine molecule or the tromethamine salt of arylpropionic acid compound has an amino functional group, and by combining with the ionic strength adjusting agent (acidic pH adjusting agent), the protonation and deprotonation can adjust and stabilize the pH value of the solution. Therefore, the present application can form a buffer system without additional addition of a buffer, thereby further simplifying the formula design, reducing the potential interference between ingredients, and avoiding the increase of osmotic pressure caused by the buffer, ensuring the stability and safety of the drug solution.

[0035] Preferably, the raw materials for preparing the nasal spray do not include a buffer.

[0036] Preferably, the acidic pH adjusting agent includes any one or a combination of at least two of phosphoric acid, tartaric acid, fumaric acid, malic acid, maleic acid, succinic acid, citric acid, lactic acid, isocitric acid, malonic acid, ascorbic acid, or anhydrous or crystalline hydrate of potassium hydrogen malate.

[0037] Preferably, the acidic pH adjusting agent includes any one or a combination of at least two of phosphoric acid, tartaric acid, fumaric acid, malic acid, maleic acid, succinic acid, or citric acid.

[0038] Preferably, the pH value of the nasal spray is 6.2-7.0, for example, it can be 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, etc.

[0039] Preferably, the osmotic pressure of the nasal spray is 300-900 mOsm / kg, for example, it can be 300 mOsm / kg, 350 mOsm / kg, 400 mOsm / kg, 450 mOsm / kg, 500 mOsm / kg, 550 mOsm / kg, 600 mOsm / kg, 650 mOsm / kg, 700 mOsm / kg, 750 mOsm / kg, 800 mOsm / kg, 850 mOsm / kg, 900 mOsm / kg, etc.

[0040] Preferably, the nasal spray is in the form of a liquid solution for spraying administration through the nasal route.

[0041] In some embodiments, the raw materials for preparing the nasal spray further include any one or a combination of at least two of an absorption enhancer, a preservative, or auxiliary stability.

[0042] In some embodiments, the absorption enhancer includes any one or a combination of at least two of dodecylmaltose, tetradecylmaltoside, polyethylene glycol-15-hydroxystearate, hydroxypropyl-B-cyclodextrin, cyclodextrin, or chitosan.

[0043] In some embodiments, the preservative includes benzalkonium bromide and / or sorbic acid;

[0044] In some embodiments, the auxiliary stabilizer includes any one or a combination of at least two of disodium edetate, mannitol, sodium heparin, hydroxyethyl starch, ethylene glycol tetraacetic acid, or ethylenediaminetetraacetic acid.

[0045] In a second aspect, the present invention provides a method for preparing a nasal spray containing an aryl propionic acid compound as described in the first aspect, the method comprising the following steps:

[0046] The raw materials for preparing nasal sprays are mixed to obtain nasal sprays containing aryl propionic acid compounds.

[0047] Thirdly, the present invention provides the use of a nasal spray containing an aryl propionic acid compound as described in the first aspect in the preparation of a medicament for treating, relieving or reducing acute or breakthrough pain or a preoperative anesthetic.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] This invention adjusts the pH of high-concentration nasal sprays to 6.0-7.0 and the osmotic pressure to 300-1000 mOsm / kg by adding an ionic strength regulator, significantly reducing the local irritation of the nasal spray to the nasal mucosa. Simultaneously, the aforementioned ionic strength regulator, which regulates both pH and osmotic pressure, ensures the long-term stability of high-concentration nasal sprays, preventing precipitation and improving biocompatibility. It achieves an optimal balance between minimizing irritation, protecting nasal mucosal function, and maintaining drug stability, thus improving user tolerance and comfort. Furthermore, this invention utilizes a self-buffering system formed by tromethorphanol and an acidity regulator, achieving solution stability without the need for an additional buffer system, avoiding the osmotic pressure increase associated with buffer systems. The nasal spray of this invention features rapid onset of action, good analgesic effect, and high safety, providing patients with acute pain with a highly effective, potent, and convenient non-opioid analgesic option. Attached Figure Description

[0050] Figure 1 These are the HE staining results of the nasal mucosa of rats in different experimental groups in Test Example 6.

[0051] Figure 2 This is a graph showing the efficacy results of different experimental groups of nasal sprays on a mouse writhing model in Test Example 7. Detailed Implementation

[0052] For further illustrating the technical means adopted by the present application and its effects, the technical solutions of the present application will be further explained in combination with the preferred embodiments of the present application, but the present application is not limited in the scope of the embodiments.

[0053] The compound having the structure shown in Formula I, the tromethamine salt of arylpropionic acid compound, and the sodium salt of arylpropionic acid compound involved in the following specific embodiments are prepared by the following methods.

[0054] (1) Preparation of the compound having the structure shown in Formula I (hereinafter referred to as Formula I compound):

[0055] The preparation method refers to the literatures "Tetrahedron Asymmetry, 2011, 22: 1125~1132" and "Synlett 2000, 6, 862~864".

[0056] (2) Preparation of the tromethamine salt of arylpropionic acid compound (compound having the structure shown in Formula II, hereinafter referred to as Formula II compound), the preparation method is as follows:

[0057] Take 4.9 g (19.7 mmol) of the compound having the structure shown in Formula I of Preparation Example 1, 2.4 g (19.7 mmol) of tromethamine, add 19.6 mL of anhydrous ethanol, control the temperature at 45°C, stir and dissolve, react for 0.5 h, add 9.8 mL of ethyl acetate and a small amount of activated carbon, control the temperature at 50°C, stir for 0.5 h, filter, add 29.4 mL of ethyl acetate to the filtrate, gradually cool to 4°C, control the temperature and stir for 4 h, filter, and the filter cake is slurried with n-hexane at 4°C for 2 h, filter, and the filter cake is dried at 50°C under vacuum for 12 h to obtain the compound having the structure shown in Formula II.

[0058] (3) Preparation of the sodium salt of arylpropionic acid compound (i.e. the sodium salt of the compound having the structure shown in Formula I, hereinafter referred to as the sodium salt of Formula I compound), the preparation method is as follows:

[0059] Take 2.97 g (12 mmol) of the compound having the structure shown in Formula I of Preparation Example 1, 0.82 g (12 mmol) of sodium ethoxide, add 20 mL of anhydrous ethanol, control the temperature at 35°C, stir and dissolve, after the reaction is completed, remove the solvent under reduced pressure, slowly drop methyl tert-butyl ether, and reduce the temperature to 5°C at a rate of 5°C / min, filter, collect the solid, and dry under reduced pressure at 45°C to obtain the sodium salt of the compound having the structure shown in Formula I.

[0060] The above-mentioned Formula I compound, Formula II compound, and sodium salt of Formula I compound can be realized by using the conventional synthesis method known in the art, and any such alternative synthesis of the compound having the structure shown in Formula I can achieve the technical effects of the present application.

[0061] The injection prescription disclosed in the patent CN111825547A involved in the following specific embodiment (HR1405-01 injection) takes the compound of formula II as the active ingredient, adds sodium chloride, tromethamine and water for injection as the adjuvant, and the concentration of the active ingredient is 10 mg / mL in free acid, and the pH is 7.4. The prescription is shown in Table 1.

[0062] Table 1

[0063]

[0064] Since the main drug has very high water solubility (>250 mg / mL), the present application develops the above-mentioned injection into a nasal spray on the basis of the above-mentioned injection. However, after simply increasing the drug concentration, we find that the formula has the following problems:

[0065] 1. With the increase of the drug concentration in the liquid medicine, the osmotic pressure of the whole solution increases, and there is no need to add sodium chloride to adjust the osmotic pressure.

[0066] 2. The addition of tromethamine increases the pH value of the liquid medicine, making it alkaline, which has poor compatibility with the slightly acidic physiological environment of the nasal cavity.

[0067] 3. The addition of tromethamine promotes the increase of the pH value of the liquid medicine, and the alkaline environment is more conducive to the existence of the compound of formula II in the form of ions in the system. The increase of the number of solutes in the whole system results in the increase of the osmotic pressure.

[0068] In order to overcome these problems, we found through in-depth research that the addition of a specific ionic strength regulator can make the key parameters of the nasal spray reach the ideal state. Specifically, the introduction of the ionic strength regulator can effectively regulate the pH and osmotic pressure of the formula, making it more in line with the physiological characteristics of the nasal cavity. This ionic strength regulator can also improve the long-term stability of the nasal spray and prolong its shelf life. Finally, through the optimization of the ratio of the ionic strength regulator, we obtain a nasal spray preparation that performs well in terms of pH, osmotic pressure and stability, successfully solving the problems of high drug concentration, unsatisfactory pH value and precipitation, etc.

[0069] The core ingredient involved in the following specific embodiment refers to the compound of formula I, the sodium salt of the compound of formula I, the compound of formula II, the compound of formula I + tromethamine or the compound of formula I + sodium hydroxide in each aqueous solution or nasal spray.

[0070] Preparation Example 1

[0071] Preparation Example 1 An aqueous solution having different concentrations (50 mg / mL, 75 mg / mL, 100 mg / mL, 125 mg / mL, 150 mg / mL in terms of the concentration of the compound of Formula I) of the core components, i.e., the sodium salt of the compound of Formula I, the compound of Formula II, the compound of Formula I + tromethamine, and the compound of Formula I + sodium hydroxide, respectively, was prepared. In the aqueous solution of the compound of Formula I and sodium hydroxide, the molar amount of sodium hydroxide was the same as that of the compound of Formula I; in the aqueous solution of the compound of Formula I and tromethamine, the molar amount of the compound of Formula I was the same as that of tromethamine. The specific preparation is shown in Table 2.

[0072] Comparative Preparation Example 1

[0073] Comparative Preparation Example 1 An aqueous solution having different concentrations (175 mg / mL in terms of the concentration of the compound of Formula I) of the core components, i.e., the sodium salt of the compound of Formula I, the compound of Formula II, the compound of Formula I + tromethamine, and the compound of Formula I + sodium hydroxide, respectively, was prepared. In the aqueous solution of the compound of Formula I and sodium hydroxide, the molar amount of sodium hydroxide was the same as that of the compound of Formula I; in the aqueous solution of the compound of Formula I and tromethamine, the molar amount of the compound of Formula I was the same as that of tromethamine. The specific preparation is shown in Table 2.

[0074] Table 2

[0075]

[0076] Test Example 1

[0077] The pH value and the osmotic pressure of the aqueous solutions obtained in the preparation examples and the comparative preparation examples were tested, and the results are shown in Tables 3 and 4, respectively.

[0078] Table 3

[0079]

[0080] Table 4

[0081]

[0082] The results show that the pH value and the osmotic pressure of the two groups of solutions, i.e., the sodium salt of the compound of Formula I and the compound of Formula I + equimolar sodium hydroxide, are basically the same, and the pH value and the osmotic pressure of the two groups of solutions, i.e., the compound of Formula II and the compound of Formula I + equimolar tromethamine, are basically the same. The higher the concentration of the drug, the higher the pH value and the osmotic pressure of the solution.

[0083] In comparison, under the same concentration of the solution, the osmotic pressure of the two groups of solutions, i.e., the compound of Formula II and the compound of Formula I + equimolar tromethamine, is lower. This shows that the combination of the compound of Formula II and the compound of Formula I + equimolar tromethamine has certain advantages in reducing the osmotic pressure, but the overall osmotic pressure is still relatively high, which may have certain irritation to the mucosa.

[0084] Test Example 2

[0085] This test example tests the osmotic pressure of the aqueous solutions obtained in the preparation examples and comparative preparation examples in different buffers.

[0086] (1) The preparation method of different buffers is as follows:

[0087] Buffer 1: 1.7 g of potassium dihydrogen phosphate, 1.775 g of anhydrous disodium hydrogen phosphate, and water is added to dilute to 1 L.

[0088] Buffer 2: 3.4 g of potassium dihydrogen phosphate, 3.55 g of anhydrous disodium hydrogen phosphate, and water is added to dilute to 1 L.

[0089] Buffer 3: 1.36 g of potassium dihydrogen phosphate, and 0.2 mol / L sodium hydroxide is used to adjust the pH to 6.8.

[0090] Buffer 4: 6.4 g of potassium dihydrogen phosphate, 18.9 g of disodium hydrogen phosphate dodecahydrate, and 0.2 mol / L sodium hydroxide is used to adjust the pH to 6.8.

[0091] Buffer 5: 6.8 g of potassium dihydrogen phosphate, 0.2363 g of sodium hydroxide.

[0092] Buffer 6: 13.6 g of potassium dihydrogen phosphate, and sodium hydroxide is used to adjust the pH to 7.0.

[0093] Buffer 7: 17.9 g of disodium hydrogen phosphate dodecahydrate is dissolved in 500 mL of water to obtain solution A; 6.8 g of potassium dihydrogen phosphate is dissolved in 500 mL of water to obtain solution B; solution A and B are mixed in a volume ratio of 2:1 until the pH of the mixture is adjusted to 7.0.

[0094] (2) Preparation of buffer-containing drug solution system:

[0095] Referring to the methods of the preparation examples and comparative preparation examples, the sodium salt of the compound of formula I, the compound of formula I + equimolar sodium hydroxide, the compound of formula II, and the compound of formula I + equimolar tromethamine are respectively dissolved in the above-mentioned seven kinds of buffers, and solutions with different concentrations (50 mg / ml, 75 mg / mL, 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL) are prepared, and the osmotic pressure of the solutions is determined, and the results are shown in Table 5.

[0096] Table 5

[0097]

[0098] The results show that the addition of each buffer system can promote the increase of the osmotic pressure. Analyzing the reason, the buffer system contains a large amount of ions, which increases the amount of solutes in the drug solution system, and further indicates that the water solution containing arylpropionic acid compounds involved in the present application cannot use the conventional method of adding a buffer system to improve the stability of the solution. Based on this, the present application adds an ionic strength regulator in the water solution containing arylpropionic acid compounds, which ensures a low osmotic pressure while the stability of the nasal spray is still good.

[0099] Example 1

[0100] Example 1 provides nasal sprays with different concentrations and different pH values, which respectively take the sodium salt of the compound of formula I, the compound of formula II, the compound of formula I + equimolar tromethamine, and the compound of formula I + equimolar sodium hydroxide as the core component. On the basis of the aqueous solutions of each preparation example and comparative preparation example, the pH of the aqueous solutions containing different core components is adjusted to 5.8, 6.0, 6.2, 6.4, 6.6, 6.8 and 7.0 by using phosphoric acid or sodium hydroxide as an ionic strength regulator, to obtain each nasal spray.

[0101] The preparation method of the above-mentioned nasal spray taking the compound of formula I + equimolar tromethamine or the compound of formula I + equimolar sodium hydroxide as the core component is as follows: the amount of tromethamine or sodium hydroxide calculated according to the concentration is added to 90% of the amount of purified water to obtain the corresponding alkaline solution; the amount of the compound of formula I calculated according to the prescription is weighed and added to the corresponding alkaline solution to dissolve, then adjusted to the specified pH value by using a phosphoric acid or sodium hydroxide solution, and finally supplemented with purified water to the theoretical weight of the drug solution.

[0102] The preparation method of the above-mentioned nasal spray taking the sodium salt of the compound of formula I or the compound of formula II as the core component is as follows: the amount of the compound of formula I calculated according to the prescription is weighed and dissolved in 90% of the amount of purified water, then adjusted to the specified pH value by using a phosphoric acid or sodium hydroxide solution, and finally supplemented with purified water to the theoretical weight of the drug solution.

[0103] Test Example 3

[0104] (1) The state of the nasal sprays with different drug contents and different pH values obtained from the examples and comparative examples was studied, and the results are shown in Table 6.

[0105] Table 6

[0106]

[0107] The results show that the compound of formula II and the compound of formula I + equimolar tromethamine are stable at a pH value of 6.0 or higher, and the sodium salt of the compound of formula I and the compound of formula I + equimolar sodium hydroxide are stable at a pH value of 6.2 or higher.

[0108] (2) The osmotic pressure of the nasal sprays with different drug contents and different pH values obtained in each example and comparative example was tested, and the results are shown in Table 7.

[0109] Table 7

[0110]

[0111] Note: "X" indicates that the solution is turbid and the osmotic pressure does not need to be measured.

[0112] The results show that, under the same concentration and pH value, the osmotic pressure of the compound of formula II and the combination of the compound of formula I and the same molar amount of tromethamine is lower, and the irritation to the nasal mucosa is lower. Therefore, preferably, the nasal spray involved in the present application comprises a tromethamine salt of an arylpropionic acid compound or a combination of an arylpropionic acid compound and tromethamine.

[0113] Test Example 4

[0114] This test example evaluates the role of different pH adjusters in optimizing the solution state of the drug solution and reducing the osmotic pressure.

[0115] Referring to the method of Example 1, the ionic strength adjuster was replaced with lactic acid, malic acid, tartaric acid, maleic acid, citric acid, fumaric acid, succinic acid, ascorbic acid, hydrochloric acid, and phosphoric acid, respectively, in turn, to prepare nasal sprays with different concentrations (50 mg / mL, 75 mg / mL, 100 mg / mL, 125 mg / mL, 150 mg / mL) and a pH value of 6.2. The solution state of the nasal sprays was observed and the osmotic pressure of the clear solution was measured, and the results are shown in Tables 8 and 9, respectively.

[0116] Table 8

[0117]

[0118] Table 9

[0119]

[0120] The results show that when malic acid, tartaric acid, maleic acid, citric acid, fumaric acid, succinic acid, or phosphoric acid is used as an ionic strength adjuster, the osmotic pressure decreases more than before pH adjustment, indicating lower irritation to the mucosa, and the solution is clear and transparent, with stable state.

[0121] Test Example 5

[0122] This test example tests the pharmacokinetics of the nasal spray.

[0123] (1) Test sample:

[0124] The following each nasal spray was obtained by using the compound of formula II as the core ingredient, adjusting the pH value to 6.2-6.4 with phosphoric acid, according to the method of Example 1.

[0125] Table 10

[0126]

[0127] (2) Test method:

[0128] Thirty-five male SD rats with a body weight of 250 g were selected and evenly divided into 7 groups, 5 rats in each group, and each group was injected or nasally sprayed with each of the above formulations. Among them, the rats in the HR1405-01 injection group were injected intravenously, the dose was 8 mg / kg, and the volume of the drug was 2 mL / kg; the rats in each nasal spray group were nasally sprayed, and the volume of the drug was 20 μL (10 μL for each nostril)

[0129] (3) In vivo drug level analysis:

[0130] The samples were collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h and 10 h after administration for experimental analysis, and the results are shown in Table 11.

[0131] Table 11

[0132]

[0133] The experimental results show that the absorption degree of the nasal spray under different concentrations is different, and the bioavailability of the nasal spray with a concentration of 100 mg / mL is the highest, reaching 90%. With the increase of the concentration of the nasal spray, the bioavailability decreases. When the exposure of each group of nasal sprays is analyzed by ratio, AUC 50 :AUC 75 :AUC 100 :AUC 125 :AUC 150 :AUC 175 ≈0.38:0.619:1:1.185:1.098:1.376, the results show that the exposure of the nasal spray does not show a strict linear relationship between the dose and the Cmax, which does not show a linear increasing trend. It shows that the nasal spray with a content of 50-150 mg / mL of the compound of formula I has a considerable drug exposure and peak drug concentration.

[0134] Test Example 6

[0135] Irritation of nasal spray:

[0136] (1) Test sample:

[0137] Following the method of Example 1, using compound II as the core component, the pH value was adjusted to 6.2-6.4 with phosphoric acid to obtain the following nasal sprays shown in Table 12.

[0138] Table 12

[0139]

[0140] (2) Test method:

[0141] Twenty-four male SD rats weighing 250 g were randomly divided into four groups of six each. Each group received a nasal spray of the aforementioned formulation. The administration volume was 20 μL (10 μL per nostril) to each group of rats. After three consecutive days of administration, the nasal region of each rat was observed (gross assessment of damage), and nasal mucosa was collected from three rats in each group for pathological staining and evaluation. After seven consecutive days of administration, the nasal region of the remaining rats was observed (gross assessment of damage), and nasal mucosa was collected from the remaining three rats for pathological staining and evaluation.

[0142] (3) Test results:

[0143] On the third day of continuous administration, rats in each experimental group were observed. The results showed that rats administered 175 mg / mL nasal spray exhibited significant sneezing behavior, while the other groups remained normal. Rats in the 175 mg / mL nasal spray group showed mild redness and swelling of the nose, and there were no significant changes in the appearance of the noses in any other group. After observation, the rats were euthanized, and the nasal mucosa was dissected for pathological staining and evaluation.

[0144] On day 7 of continuous administration, rats in each experimental group were observed. Results showed that sneezing was more pronounced after administration of the 175 mg / mL nasal spray compared to after 3 consecutive days of administration, while the other groups remained normal. The 175 mg / mL nasal spray group showed increased nasal redness and swelling, but no significant changes in the gross appearance of the noses were observed in any other group. After observation, the rats were euthanized, and their nasal mucosa was dissected for pathological staining and evaluation.

[0145] like Figure 1 As shown, rats were administered nasal sprays at concentrations of 100 mg / mL, 125 mg / mL, 150 mg / mL, and 175 mg / mL for 3 and 7 consecutive days. In the 175 mg / mL group, after 3 days of continuous administration, mild damage and significant inflammatory infiltration of the nasal mucosa were observed. In the other groups, the nasal mucosa remained intact without damage or inflammatory infiltration. In the 175 mg / mL group, after 7 days of continuous administration, significant damage and increased inflammatory infiltration of the nasal mucosa were observed. In the other groups, the nasal mucosa remained intact without significant damage or inflammatory effect.

[0146] Test Example 7

[0147] Pharmacodynamic studies:

[0148] (1) Sample to be tested: 100 mg / mL nasal spray-3 from test example 5.

[0149] (2) Test method:

[0150] The analgesic efficacy of the nasal spray was evaluated using an acetic acid writhing model. Twenty-two male ICR mice were randomly divided into two groups: a model group and a treatment group.

[0151] The mice in the treatment group were given 100 mg / mL nasal spray-3 in each nostril as in test case 5, at a dose of 2 μL / well; the mice in the model group were treated with an equal volume of sodium chloride injection in their nasal cavities.

[0152] Thirty minutes later, each mouse was injected intraperitoneally with 1% glacial acetic acid (200 μL / mouse) to construct an acetic acid writhing model. The number of writhing episodes in the mice within 15 minutes after modeling was recorded, and the analgesia rate was calculated to evaluate the analgesic effect of the drug.

[0153] Analgesia rate = (average number of writhing responses in the model group - average number of writhing responses in the experimental group) / average number of writhing responses in the model group × 100%.

[0154] (3) Test results:

[0155] Test results are as follows Figure 2 As shown, compared with the model group, the number of writhing movements in the mice treated within 15 minutes of modeling was significantly reduced, and the analgesia rate reached 59.4%, proving that the nasal spray of the present invention has a significant analgesic effect on the acetic acid writhing model in mice.

[0156] Test Example 8

[0157] Stability study of nasal spray:

[0158] (1) Sample to be tested:

[0159] Following the method of Example 1, using compound II and compound I + tromethamine as the core components, the pH value was adjusted to 6.2-6.4 with phosphoric acid to obtain the various nasal sprays shown in Tables 13-14.

[0160] Table 13

[0161]

[0162] Table 14

[0163]

[0164] (2) Test method:

[0165] The nasal sprays of the above-mentioned prescriptions 1-8 are respectively placed at 2-8℃, 25℃, 30℃ and 40℃. The samples placed at 40℃ are respectively sampled at 1, 2, 3 and 6 months to study the drug content, related substances, visible foreign matter, insoluble particles, pH value and osmotic pressure; the samples placed at 2-8℃, 25℃ and 30℃ are respectively sampled at 1, 2, 3 and 6 months to study the drug content, related substances, visible foreign matter, insoluble particles, pH value and osmotic pressure.

[0166] The nasal sprays related to the present application have small changes in the parameters such as related substances, visible foreign matter, insoluble particles, pH value and osmotic pressure after being placed under different conditions, and have excellent stability.

[0167] The applicant declares that the technical solutions of the present application are illustrated by the above-mentioned embodiments, but the present application is not limited to the above-mentioned embodiments, i.e. it does not mean that the present application must rely on the above-mentioned embodiments to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of each raw material of the product of the present application, addition of auxiliary ingredients, selection of specific modes, etc. all fall within the protection scope and disclosure scope of the present application.

[0168] The preferred embodiments of the present application are described in detail above, but the present application is not limited to the specific details in the above-mentioned embodiments. Within the technical concept scope of the present application, the technical solutions of the present application can be subjected to various simple modifications, and these simple modifications all belong to the protection scope of the present application.

[0169] In addition, it should be noted that each specific technical feature described in the above-mentioned specific embodiments can be combined by any suitable method without contradiction. In order to avoid unnecessary repetition, the present application does not further illustrate various possible combination methods.

Claims

1. A nasal spray containing an arylpropionic acid compound, characterized in that, The preparation raw materials of the nasal spray include any one of the following components: (1) a pharmaceutically acceptable salt of an arylpropionic acid compound, an ionic strength adjusting agent, and water; (2) an arylpropionic acid compound, a base, an ionic strength adjusting agent, and water; The structure of the arylpropionic acid compound is shown in Formula I; Formula I; In component (1), the concentration of the pharmaceutically acceptable salt of the arylpropionic acid compound in the nasal spray is 50-150 mg / mL, calculated as the free acid of the arylpropionic acid compound; In component (2), the concentration of the arylpropionic acid compound in the nasal spray is 50-150 mg / mL; The ionic strength adjusting agent is used to adjust the pH of the nasal spray to 6.0-7.0 and the osmotic pressure of the nasal spray to 300-1000 mOsm / kg.

2. The nasal spray of claim 1, wherein, The pharmaceutically acceptable salt of the arylpropionic acid compound in component (1) includes a sodium salt or a tromethamine salt of the arylpropionic acid compound, preferably a tromethamine salt of the arylpropionic acid compound; The structure of the tromethamine salt of the arylpropionic acid compound is shown in Formula II; Formula II.

3. The nasal spray of claim 1, wherein, The base in component (2) includes tromethamine and / or sodium hydroxide.

4. The nasal spray of claim 1 or 3, wherein, The molar ratio of the arylpropionic acid compound to the base in component (2) is 1:0.5-1:2, preferably 1:0.9-1:

1.

5. The nasal spray of any one of claims 1-4, wherein, The ionic strength adjusting agent includes a pH adjusting agent; Preferably, the pH adjusting agent includes an acidic pH adjusting agent.

6. The nasal spray of claim 5, wherein, The acidic pH adjusting agent includes any one of anhydrous or crystalline hydrate of phosphoric acid, tartaric acid, fumaric acid, malic acid, maleic acid, succinic acid, citric acid, lactic acid, isocitric acid, malonic acid, ascorbic acid, or potassium hydrogen malate, or a combination of at least two thereof; Preferably, the acidic pH adjusting agent includes any one of phosphoric acid, tartaric acid, fumaric acid, malic acid, maleic acid, succinic acid, or citric acid, or a combination of at least two thereof.

7. The nasal spray of any one of claims 1-6, wherein, The pH of the nasal spray is 6.0-6.8, preferably 6.2-6.8; Preferably, the osmotic pressure of the nasal spray is 300-900 mOsm / kg.

8. The nasal spray of any one of claims 1-7, wherein, The preparation raw materials of the nasal spray further include any one of an absorption enhancer, a preservative, or auxiliary stability, or a combination of at least two thereof; Preferably, the absorption enhancer includes any one of dodecylmaltoside, tetradecylmaltoside, polyethylene glycol-15-hydroxystearate, hydroxypropyl-B-cyclodextrin, cyclodextrin, or chitosan, or a combination of at least two thereof; Preferably, the preservative includes benzalkonium bromide and / or sorbic acid; Preferably, the auxiliary stability includes any one of disodium edetate, mannitol, heparin sodium, hydroxyethyl starch, ethylene glycol tetraacetic acid, or ethylenediaminetetraacetic acid, or a combination of at least two thereof.

9. A method for preparing the arylpropionic acid-containing nasal spray according to any one of claims 1 to 8, characterized in that, The preparation method includes the following steps: Mixing the preparation raw materials of the nasal spray to obtain the nasal spray containing the arylpropionic acid compound.

10. Use of the nasal spray containing the arylpropionic acid compound according to any one of claims 1-9 in the preparation of a drug for treating, relieving, or alleviating acute or breakthrough pain or a preoperative anesthetic drug.

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