A nasal spray composition for treating brain edema and a method of preparing and using the same

Abstract

A nasal spray composition for treating cerebral edema comprises a pyridine sulfonamide phosphate compound represented by formula 1 or a pharmaceutically acceptable salt thereof. The nasal spray of the present application has the advantages of high brain penetration, strong efficacy, few side effects, good patient compliance, convenient carrying and use, etc., significantly improving the effectiveness and safety of the drug. In addition, the nasal spray composition of the present application also contains a stabilizer, rhamnose. As a stabilizer, rhamnose can greatly improve the stability of the nasal spray composition.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a nasal spray composition with pyridine sulfonamide phosphate compounds or their pharmaceutically acceptable salts as the main components. This invention also relates to the preparation method and use of the composition. Background Technology

[0002] Cerebral edema is a pathological condition characterized by increased water content in the brain, leading to an enlarged brain volume. It is a response of brain tissue to various pathogenic factors. This condition typically results in impaired neurological function, increased intracranial pressure, and ultimately, direct compression of brain tissue and blood vessels. Symptoms vary depending on the location and severity of the edema and generally include headache, nausea, vomiting, seizures, drowsiness, visual disturbances, dizziness, and in severe cases, coma and death. Although current medical technologies can enable some patients to achieve successful recanalization through early endovascular treatment, a poor prognosis and even death still occur in some cases.

[0003] The inventors of this patent discovered in previous research that a pyridine sulfonamide phosphate compound has a good diuretic effect (patent publication number CN110606860B) and can be administered via injection to treat cerebral edema caused by various reasons and prevent brain herniation (patent application publication number CN114796241A). A preferred compound I-1 from this class of pyridine sulfonamide phosphate compounds was then subjected to preclinical systematic research as a Class 1 new drug. Preclinical pharmacodynamic studies showed that this type of drug, administered via injection, has a good therapeutic effect on cerebral edema. Considering the pathogenesis of cerebral edema and the convenience of medication for patients, the inventors began to focus on the development of a nasal spray formulation.

[0004] However, aqueous solutions of these pyridine sulfonamide phosphate compounds are heat-labile; for example, compound I-1 injection requires refrigeration at 2–8°C for long-term storage. Considering that nasal sprays are mostly used by patients outside of hospitals, stringent storage conditions not only cause inconvenience but also increase the cost of transportation and storage.

[0005] Therefore, there is an urgent need to develop a nasal spray containing pyridine sulfonamide phosphate compounds that is stable and easy to manufacture. Summary of the Invention

[0006] The purpose of this invention is to provide a nasal spray composition of a pyridine sulfonamide phosphate compound that is stable and easy to manufacture, enabling the product to be better applied in the treatment of cerebral edema. A nasal spray composition for treating cerebral edema is characterized by comprising a pyridine sulfonamide phosphate compound of Formula 1 or a pharmaceutically acceptable salt thereof;

[0007]

[0008] Where X is O or CH2, or X does not exist; Y is CH2, or Y does not exist; when neither X nor Y exists, O is directly connected to P; when X exists but Y does not exist, X is directly connected to O; when Y exists but X does not exist, Y is directly connected to P.

[0009] Optionally, the nasal spray composition for treating cerebral edema further comprises the stabilizer rhamnose;

[0010] Optionally, the pyridine sulfonamide phosphate compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0011]

[0012] Optionally, the nasal spray composition of the present invention for treating cerebral edema further contains the solvent water.

[0013] Optionally, in 100 mL of the nasal spray composition, the content of the pyridine sulfonamide phosphate compound of Formula 1 or its pharmaceutically acceptable salt is 0.1 to 20 g, preferably 0.5 to 10 g;

[0014] Optionally, the content of rhamnose in the 100mL nasal spray composition is 0.05-10g, preferably 0.1-5g.

[0015] Optionally, the nasal spray composition further includes a viscosity modifier and a preservative.

[0016] Preferably, the viscosity modifier is one or more of poloxamer, gelatin, chitosan, gum arabic, carboxymethyl cellulose, alginate, polyethylene glycol, propylene glycol, and glycerin, with poloxamer being the most preferred.

[0017] Preferably, the preservative is one or more of benzalkonium chloride, benzoic acid, boric acid, p-hydroxybenzoate, phenols, chlorinated phenolic compounds, and combinations thereof, with benzalkonium chloride being the most preferred.

[0018] Preferably, in the 100mL nasal spray composition, the content of the viscosity modifier is 0.1-10g, more preferably 0.2-5g;

[0019] Preferably, the preservative content in the 100mL nasal spray composition is 0.005-5g, more preferably 0.01-2g.

[0020] Optionally, the pharmaceutically acceptable salt includes a salt formed by a compound of formula 1 and an organic base, or a salt formed by a compound of formula 1 and a basic amino acid, or a metal salt of a compound of formula 1.

[0021] Optionally, the organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine, or diisopropylethylamine;

[0022] Optionally, the metal salt of the compound of Formula 1 is selected from the alkali metal salt, alkaline earth metal salt or aluminum salt of the compound of Formula 1.

[0023] Optionally, the alkali metal salt of the compound of formula 1 is selected from the sodium or potassium salt of the compound of formula 1;

[0024] Optionally, the alkaline earth metal salt of the compound of Formula 1 is selected from the calcium, magnesium, or barium salts of the compound of Formula 1.

[0025] Optionally, the pH of the nasal spray composition is 4.0 to 8.0, preferably 5.5 to 7.0;

[0026] Preferably, the osmotic pressure of the nasal spray composition is 280–330 mOsmol / kg, more preferably 285–310 mOsmol / kg;

[0027] Preferably, the nasal spray composition of the present invention for treating cerebral edema comprises the following components:

[0028] In the 100mL nasal spray composition, the active pharmaceutical ingredient (API) of formula I-1 or its pharmaceutically acceptable salt is 0.1–20g, the stabilizer rhamnose is 0.05–10g, the viscosity modifier is 0.1–10g, and the preservative is 0.005–5g.

[0029] Optionally, a pH adjuster is added to make the pH of the nasal spray composition 4.0 to 8.0; optionally, an osmotic pressure adjuster is added to make the osmotic pressure of the nasal spray composition 280 to 330 mOsmol / kg.

[0030] Preferably, the osmotic pressure regulator used to adjust the osmotic pressure of the nasal spray composition is one or more of sodium chloride, glycerin, anhydrous glucose, propylene glycol, potassium chloride, sorbitol, mannitol, and combinations thereof, preferably sodium chloride.

[0031] Optionally, the pH adjuster used to adjust the pH of the nasal spray composition is one or more of hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid and its salts, citric acid and its salts, malic acid and its salts, fumaric acid and its salts, tartaric acid and its salts, phosphoric acid and its salts, boric acid and its salts, carbonic acid and its salts, and acetic acid and its salts, preferably hydrochloric acid.

[0032] In this invention, rhamnose (L-rhamnose monohydrate, CAS: 6155-35-7), also known as mannomethyl glycoside, is a component of plant cell walls and various glycosides, and is a white to off-white crystalline powder. Rhamnose is commonly used to determine intestinal permeability, synthesize cardiotonic drugs, and can be used as a sweetener and in the production of flavorings and fragrances. However, its application as a stabilizer in the pharmaceutical field has not been reported in the literature. In stabilizer screening experiments, researchers found that the addition of rhamnose significantly improved the stability of pyridine sulfonamide phosphate compounds in aqueous solutions.

[0033] In another aspect, the present invention provides the use of the above-described nasal spray composition for treating cerebral edema in the preparation of a medicament for treating cerebral edema.

[0034] On the other hand, the present invention provides a method for preparing the above-mentioned nasal spray composition for treating cerebral edema, which includes the following preparation steps:

[0035] Step S1: Dissolve the stabilizer in water;

[0036] Step S2: Add the active pharmaceutical ingredient, pyridine sulfonamide phosphate compound or its pharmaceutically acceptable salt, optional preservative, and optional viscosity modifier to the aqueous solution;

[0037] Step S3: Add an optional pH adjuster to adjust the pH of the solution;

[0038] Step S4: Add an optional osmotic pressure regulator to adjust the osmotic pressure.

[0039] Preferably, the preparation method of the nasal spray composition for treating cerebral edema of the present invention includes the following steps:

[0040] a. Take 60% to 90% of the prescribed amount of water for injection that has been boiled and cooled to room temperature, add the stabilizer, and stir until completely dissolved;

[0041] b. Keep the room temperature, add the active ingredient, preservative, and viscosity modifier in sequence, stir to dissolve, and then add water for injection to make up to 95% of the total volume;

[0042] c. Add a pH adjuster to adjust the pH of the solution to 5.5-7.0;

[0043] d. Add an osmotic pressure regulator to adjust the osmotic pressure to 0.285-0.310 Osmol / kg, and replenish the remaining water for injection according to the prescription;

[0044] e. After sterilization by two-stage 0.22μm PES filter membrane filtration, the product is filled and packaged.

[0045] On the other hand, the present invention provides the use of the above-described nasal spray composition for treating cerebral edema in the preparation of a medicament for treating cerebral edema.

[0046] Compared with the prior art, the present invention has the following advantages:

[0047] 1. This invention is the first to use rhamnose as a stabilizer in nasal spray formulations of pyridine sulfonamide phosphate compounds or their pharmaceutically acceptable salts. Stability studies show that under accelerated and long-term conditions, the stability of samples with added rhamnose is significantly improved compared to those without, greatly enhancing the convenience of product transportation and storage.

[0048] 2. The nasal spray composition of the present invention is simple and convenient to prepare, and can effectively control production costs and reduce patients' expenses during treatment.

[0049] 3. The nasal spray composition of the present invention can improve the brain penetration rate of drugs, and has the advantages of strong efficacy, few side effects, good patient compliance, and convenient carrying and use, which significantly improves the effectiveness and safety of drugs. Detailed Implementation

[0050] The technical solution of the present invention will be clearly and completely described below by way of embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0051] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0052] Example 1

[0053] This embodiment provides a method for preparing a nasal spray composition, wherein the composition is a nasal spray of compound of formula I-1 (hereinafter referred to as XH-6003), wherein the content of XH-6003 is 100 mg / mL;

[0054] The preparation method is as follows:

[0055] a. Take 800ml of boiled and cooled water for injection to room temperature, add 20g of rhamnose, and stir until completely dissolved;

[0056] b. Keep the room temperature, add 100g of XH-6003, 1g of benzalkonium chloride, and 2g of poloxamer, stir to dissolve, and then add water for injection to make up to 950ml.

[0057] c. Add an appropriate amount of hydrochloric acid to adjust the pH of the solution to 7.0;

[0058] d. Add water for injection to a total of 1000ml;

[0059] e. After sterilization by filtration through two-stage 0.22μm PES membranes, the solution is filled into the nasal spray device and then packaged.

[0060] Example 2

[0061] This embodiment provides a method for preparing a nasal spray composition, wherein the composition is XH-6003 nasal spray, and the content of XH-6003 is 50 mg / mL;

[0062] The preparation method is as follows:

[0063] a. Take 800ml of boiled and cooled water for injection to room temperature, add 10g of rhamnose, and stir until completely dissolved;

[0064] b. Keep at room temperature, add 50g of XH-6003, 1g of benzalkonium chloride, and 2g of gelatin. Stir to dissolve, then add water for injection to bring the volume to 950ml.

[0065] c. Add an appropriate amount of hydrochloric acid to adjust the pH of the solution to 6.0;

[0066] d. Add 5g of sodium chloride and bring the water for injection to 1000ml;

[0067] e. After sterilization by filtration through two-stage 0.22μm PES membranes, the solution is filled into the nasal spray device and then packaged.

[0068] Example 3

[0069] This embodiment provides a method for preparing a nasal spray composition, wherein the composition is XH-6003 nasal spray, and the content of XH-6003 is 25 mg / mL;

[0070] The preparation method is as follows:

[0071] a. Take 800ml of boiled and cooled water for injection to room temperature, add 5g of rhamnose, and stir until completely dissolved;

[0072] b. Keep the room temperature, add 25g of XH-6003, 1g of benzalkonium chloride, and 2g of poloxamer, stir to dissolve, and then add water for injection to make up to 950ml.

[0073] c. Add an appropriate amount of hydrochloric acid to adjust the pH of the solution to 6.0;

[0074] d. Add 7.5g of sodium chloride and bring the volume of water for injection to 1000ml;

[0075] e. After sterilization by filtration through two-stage 0.22μm PES membranes, the solution is filled into the nasal spray device and then packaged.

[0076] Example 4

[0077] This embodiment provides a method for preparing a nasal spray composition, wherein the composition is XH-6003 nasal spray, and the content of XH-6003 is 5 mg / mL;

[0078] The preparation method is as follows:

[0079] a. Take 800ml of boiled and cooled water for injection to room temperature, add 1g of rhamnose, and stir until completely dissolved;

[0080] b. Keep the room temperature, add 5g of XH-6003, 1g of benzalkonium chloride, and 2g of poloxamer, stir to dissolve, and then add water for injection to make up to 950ml.

[0081] c. Add an appropriate amount of hydrochloric acid to adjust the pH of the solution to 5.5;

[0082] d. Add 8.5g of sodium chloride and bring the volume of water for injection to 1000ml;

[0083] e. After sterilization by filtration through two-stage 0.22μm PES membranes, the solution is filled into the nasal spray device and then packaged.

[0084] Example 5

[0085] This embodiment provides a method for preparing a nasal spray composition, wherein the composition is XH-6003 nasal spray, and the content of XH-6003 is 50 mg / mL;

[0086] The preparation method is as follows:

[0087] a. Take 800ml of boiled and cooled water for injection to room temperature, add 50g of rhamnose, and stir until completely dissolved;

[0088] b. Keep the room temperature, add 50g of XH-6003, 1g of benzalkonium chloride, and 2g of poloxamer, stir to dissolve, and then add water for injection to make up to 950ml.

[0089] c. Add an appropriate amount of boric acid to adjust the pH of the solution to 6.0;

[0090] d. Add 5g of sodium chloride and bring the water for injection to 1000ml;

[0091] e. After sterilization by filtration through two-stage 0.22μm PES membranes, the solution is filled into the nasal spray device and then packaged.

[0092] Example 6

[0093] This embodiment provides a method for preparing a nasal spray composition, wherein the composition is XH-6003 nasal spray, and the content of XH-6003 is 50 mg / mL;

[0094] The preparation method is as follows:

[0095] a. Take 800ml of boiled and cooled water for injection to room temperature, add 10g of rhamnose, and stir until completely dissolved;

[0096] b. Keep the room temperature, add 50g of XH-6003, 20g of benzalkonium chloride, and 2g of poloxamer, stir to dissolve, and then add water for injection to make up to 950ml.

[0097] c. Add an appropriate amount of hydrochloric acid to adjust the pH of the solution to 6.0;

[0098] d. Add 5g of sodium chloride and bring the water for injection to 1000ml;

[0099] e. After sterilization by filtration through two-stage 0.22μm PES membranes, the solution is filled into the nasal spray device and then packaged.

[0100] In the following embodiments, the structural formula of XH-6003-M is as follows:

[0101]

[0102] Example 7

[0103] This embodiment provides a method for preparing a nasal spray composition, wherein the composition is XH-6003 nasal spray, and the content of XH-6003 is 50 mg / mL;

[0104] The preparation method is as follows:

[0105] a. Take 800ml of boiled and cooled water for injection to room temperature, add 10g of rhamnose, and stir until completely dissolved;

[0106] b. Keep the room temperature, add 50g of XH-6003, 0.1g of benzalkonium chloride, and 50g of poloxamer. Stir to dissolve, then add water for injection to make up to 950ml.

[0107] c. Add an appropriate amount of hydrochloric acid to adjust the pH of the solution to 6.0;

[0108] d. Add 5g of sodium chloride and bring the water for injection to 1000ml.

[0109] e. After sterilization by two-stage 0.22μm PES filter membrane filtration, the solution is filled into the nasal spray device and then packaged.

[0110] Example 8: Comparison of stability test results of XH-6003 nasal spray under accelerated and long-term tests

[0111] The sample prepared in Example 2 was used as the experimental group, and the sample without rhamnose and with the same other components as in Example 2 was used as the control group. The samples were stored under accelerated (40℃±2℃ / 75%±5%) and long-term (25℃±2℃ / 60%±5%) test conditions. The properties, content, pH value and related substances of the samples were measured at 0, 1 month, 3 months and 6 months. The test results are shown in Table 1 and Table 2.

[0112] Table 1. Accelerated Stability Study Results of XH-6003 Nasal Spray (40℃±2℃ / 75%±5%)

[0113]

[0114]

[0115] Table 2. Long-term stability test results of XH-6003 nasal spray (25℃±2℃ / 60%±5%)

[0116]

[0117]

[0118] The data above show that in the control group sample without rhamnose, the related substance XH-6003-M increased rapidly in the stability study, increasing 23-fold under accelerated conditions (40℃±2℃ / 75%±5%) after 3 months; and also significantly increasing under long-term conditions (25℃±2℃ / 60%±5%) after 6 months. Furthermore, the growth trend of related substance XH-6003-E in the control group sample was also quite obvious, increasing from 0.22% to 0.72% under accelerated conditions for 3 months; and from 0.22% to 0.45% under long-term conditions for 6 months.

[0119] For the experimental group samples with added rhamnose, the related substance XH-6003-E showed almost no increase; although the related substance XH-6003-M increased, the rate of increase was slow, increasing only from 0.28% to 0.65% over 6 months under accelerated conditions; and only from 0.28% to 0.35% under long-term conditions over 6 months.

[0120] Based on the above data, it can be seen that the addition of rhamnose significantly improves the stability of XH-6003 nasal spray, making it suitable for room temperature storage and greatly enhancing the convenience of the product during transportation and storage.

[0121] Example 9: Comparative Study of Brain Penetration of XH-6003 Nasal Spray and XH-6003 Injection

[0122] SD rats, with equal numbers of males and females, were randomly divided into groups of 6 rats each at each time point. Each group received an intravenous injection of XH-6003 solution (i.e., an aqueous solution of XH-6003, 10 mg / kg, dosage per animal) via the tail vein. After administering a diluted product of XH-6003 nasal spray prepared in Example 1 (25 mg / ml, 100 uL per dose, approximately 2.5 mg per animal), brain tissue and cerebrospinal fluid were collected at different time points, and the content of the active metabolite XH-6003-M was detected by LC-MS / MS.

[0123] The results are shown in Table 3. When the drug was administered via nasal spray, the drug content in the brain tissue and cerebrospinal fluid of SD rats was significantly increased compared with that administered via injection, indicating that the nasal spray had a higher brain penetration rate and predicted that it would have a stronger therapeutic effect on cerebral edema.

[0124] Table 3. Average drug content-time data in brain tissue and cerebrospinal fluid of SD rats.

[0125]

[0126] Note: "BLQ" indicates below the lower limit of quantitation.

Claims

1. A nasal spray composition for treating cerebral edema, characterized in that, The pyridine sulfonamide phosphate compound or its pharmaceutically acceptable salt as shown in Formula 1 is included. Where X is O or CH2, or X does not exist; Y is CH2, or Y does not exist; when neither X nor Y exists, O is directly connected to P; when X exists but Y does not exist, X is directly connected to O; when Y exists but X does not exist, Y is directly connected to P.

2. The nasal spray composition for treating cerebral edema according to claim 1, characterized in that, The nasal spray composition contains the stabilizer rhamnose.

3. The nasal spray composition for treating cerebral edema according to claim 1 or 2, characterized in that, The pyridine sulfonamide phosphate compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

4. The nasal spray composition for treating cerebral edema according to any one of claims 1-3, characterized in that, The nasal spray composition contains the solvent water. Optionally, in 100 mL of the nasal spray composition, the content of the pyridine sulfonamide phosphate compound of Formula 1 or its pharmaceutically acceptable salt is 0.1 to 20 g, preferably 0.5 to 10 g; Optionally, the content of rhamnose in the 100mL nasal spray composition is 0.05-10g, preferably 0.1-5g.

5. The nasal spray composition for treating cerebral edema according to any one of claims 1-4, characterized in that, The nasal spray composition also includes a viscosity modifier and a preservative. Preferably, the viscosity modifier is one or more of poloxamer, gelatin, chitosan, gum arabic, carboxymethyl cellulose, alginate, polyethylene glycol, propylene glycol, and glycerin, with poloxamer being the most preferred. Preferably, the preservative is one or more of benzalkonium chloride, benzoic acid, boric acid, p-hydroxybenzoate, phenols, chlorinated phenolic compounds, and combinations thereof, with benzalkonium chloride being the most preferred. Preferably, in the 100mL nasal spray composition, the content of the viscosity modifier is 0.1-10g, more preferably 0.2-5g; Preferably, the preservative content in the 100mL nasal spray composition is 0.005-5g, more preferably 0.01-2g.

6. The nasal spray composition for treating cerebral edema according to any one of claims 1-5, characterized in that, The pharmaceutically acceptable salts include salts formed by a compound of formula 1 and an organic base, or salts formed by a compound of formula 1 and a basic amino acid, or metal salts of a compound of formula 1.

7. The nasal spray composition for treating cerebral edema according to claim 6, characterized in that, The organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine, or diisopropylethylamine; Optionally, the metal salt of the compound of Formula 1 is selected from the alkali metal salt, alkaline earth metal salt or aluminum salt of the compound of Formula 1. Optionally, the alkali metal salt of the compound of formula 1 is selected from the sodium or potassium salt of the compound of formula 1; Optionally, the alkaline earth metal salt of the compound of Formula 1 is selected from the calcium, magnesium, or barium salts of the compound of Formula 1.

8. The nasal spray composition for treating cerebral edema according to any one of claims 1-7, characterized in that, The pH of the nasal spray composition is 4.0 to 8.0, preferably 5.5 to 7.0; Preferably, the osmotic pressure of the nasal spray composition is 280–330 mOsmol / kg, more preferably 285–310 mOsmol / kg; Preferably, the osmotic pressure regulator used to adjust the osmotic pressure of the nasal spray composition is one or more of sodium chloride, glycerin, anhydrous glucose, propylene glycol, potassium chloride, sorbitol, mannitol, and combinations thereof, preferably sodium chloride.

9. The nasal spray composition for treating cerebral edema according to any one of claims 1-8, characterized in that, The pH adjuster used to adjust the pH of the nasal spray composition is one or more of the following: hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid and its salts, citric acid and its salts, malic acid and its salts, fumaric acid and its salts, tartaric acid and its salts, phosphoric acid and its salts, boric acid and its salts, carbonic acid and its salts, and acetic acid and its salts, with hydrochloric acid being preferred.

10. Use of the nasal spray composition for treating cerebral edema as described in any one of claims 1-9 in the preparation of a medicament for treating cerebral edema.

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