Nasal spray containing Darlirasone as well as preparation method and application of nasal spray

Abstract

The invention discloses a nasal spray containing Darliflosan as well as a preparation method and application thereof, the nasal spray is prepared from the following raw materials: 3%-4.2% of Darliflosan or pharmaceutically acceptable salt thereof, 1%-3% of a suspending aid, 2%-6% of an osmotic pressure regulator, 2%-5% of a solvent and 0.003%-0.012% of a surfactant, and the particle size of the Darliflosan or pharmaceutically acceptable salt thereof is D90lt; 5 [mu] m; the suspending aid is one or more of a microcrystalline cellulose and carboxymethyl cellulose sodium co-treatment substance, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, xanthan gum, carbomer and povidone. The nasal spray disclosed by the invention has the characteristics of good stability, stable dosage, quick response and the like, has the advantages of avoiding the first-pass effect of the liver, quick absorption, quick response, high bioavailability, realization of brain targeting and the like, is convenient to use, can be sprayed once in each nasal cavity before sleep for a patient with dysphagia, and is convenient to take.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and more particularly, the present application relates to a nasal spray containing daridorexant hydrochloride and a preparation method and application thereof. BACKGROUND

[0002] Daridorexant ((S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone, structural formula as shown) is an oral drug for treating adult insomnia patients characterized by difficulty falling asleep and / or difficulty maintaining sleep. Daridorexant is a dual orexin receptor antagonist that can simultaneously act on orexin type 1 receptor (OX1R) and orexin type 2 receptor (OX2R), blocking the binding of orexin to its receptors, which is a wake-promoting neuropeptide produced in the lateral hypothalamic area and plays an important regulatory role in sleep-wake rhythm. By blocking the action of orexin, daridorexant can reduce the state of excessive activity, thereby promoting sleep. Figure 1

[0003] On April 7, 2022, the U.S. Food and Drug Administration (FDA) approved daridorexant tablets (trade name QUVIVIQ) of IDORSIA for the treatment of adult insomnia patients characterized by difficulty falling asleep and / or difficulty maintaining sleep, and the original research was approved for listing in China on June 17, 2025. However, tablets are not friendly to patients with difficulty swallowing. SUMMARY

[0004] Therefore, the purpose of the present application is to provide a nasal spray containing daridorexant that is friendly to patients with difficulty swallowing.

[0005] The technical solution for achieving the above-mentioned purpose of the application includes the following.

[0006] In a first aspect of the present application, a nasal spray containing daridorexant is provided, which is made from raw materials including the following weight percentages: Daridorexant or a pharmaceutically acceptable salt thereof 3%~4.2% Suspending agent 1%~3% Osmotic pressure regulator 2%~6% Solvent 2%~5% Surfactant 0.003%~0.012% The balance is water. ​The particle size D90 of the daridorexant or the pharmaceutically acceptable salt thereof is less than 5 μm; the suspending agent is one or more of microcrystalline cellulose sodium carboxymethyl cellulose co-treatment, sodium carboxymethyl cellulose, hypromellose, xanthan gum, carbomer, povidone.

[0007] In a second aspect of the present application, a preparation method of the above-mentioned nasal spray containing daridorexant is provided, comprising the following steps: (1) crushing daridorexant or a pharmaceutically acceptable salt thereof; (2) adding an osmotic pressure regulator and a suspending agent into part of water and dissolving; (3) adding a surfactant, a solvent and the crushed raw material drug of step (1) into the remaining water and homogeneously dispersing; (4) adding the solution of step (3) into the solution of step (2) and homogeneously stirring and dispersing to obtain the nasal spray.

[0008] In a third aspect of the present application, the above-mentioned nasal spray containing daridorexant is used for treating sleep onset difficulties and / or sleep maintenance difficulties.

[0009] The inventors of the present application found that, in the preparation of the nasal spray containing daridorexant, the particle size of the raw material drug and the selection of the excipients (especially the suspending agent) can significantly affect the dissolution rate and the uniformity of drug delivery, therefore, the inventors used daridorexant or a pharmaceutically acceptable salt thereof with a certain particle size as the active ingredient, and screened the suspending agent and other excipients (suspending agent, surfactant, solvent, osmotic pressure regulator, etc.) that can be compatible with the active ingredient, successfully prepared the nasal spray with stable sedimentation volume ratio, uniform delivery dose and high dissolution rate, which has the characteristics of good stability, stable drug delivery amount, fast onset, etc.

[0010] Compared with the marketed oral tablets, the nasal spray of the present application has the advantages of avoiding the first pass effect of the liver, rapid absorption, fast onset, high bioavailability, brain targeting, etc.

[0011] The nasal spray of the present application is convenient to use, and for patients with difficulty in swallowing, it can be used by spraying one time in each nasal cavity before sleep, which is convenient for drug use. BRIEF DESCRIPTION OF DRAWINGS

[0012] Figure 1 is the chemical structural formula of daridorexant.

[0013] Figure 2 is the microscopic image of the raw material drug daridorexant hydrochloride (*500 times).

[0014] Figure 3 is the microscopic image of the raw material drug in the nasal spray solution of sample 2 of the present application (*500 times).

[0015] Figure 4Raman scan of Dalireline hydrochloride as a raw material.

[0016] Figure 5 Raman scan of sample 2 nasal spray solution.

[0017] Figure 6 Raman scan comparison of Dalireline hydrochloride as a raw material and sample 2 nasal spray solution.

[0018] Figure 7 XRD scan of Dalireline hydrochloride as a raw material.

[0019] Figure 8 XRD scan of sample 2 nasal spray solution.

[0020] Figure 9 XRD scan comparison of Dalireline hydrochloride as a raw material and sample 2 nasal spray solution. DETAILED DESCRIPTION

[0021] In order to facilitate the understanding of the present application, a more comprehensive description of the present application will be given below. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in this application, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0023] The experimental methods in the following examples, unless otherwise specified, are generally carried out according to the conventional conditions, such as the conditions described in Green and Sambrook et al., Molecular Cloning: A Laboratory Manual, 2013, or according to the conditions recommended by the manufacturer. The various common chemical reagents used in the examples are commercially available products.

[0024] In some embodiments of the present application, a nasal spray containing Dalireline is disclosed, which is made from raw materials including the following weight percentages: Dalireline or a pharmaceutically acceptable salt thereof 3%~4.2% Suspending agent 1%~3% Osmotic pressure regulator 2%~6% Solvent 2%~5% Surfactant 0.003%~0.012% The remainder is water; The particle size D90 of the dali-resen or its pharmaceutically acceptable salt is <5 μm; the suspending agent is one or more of the following: microcrystalline cellulose sodium carboxymethyl cellulose co-treated product, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, xanthan gum, carbomer, and povidone.

[0025] In one embodiment, the nasal spray is made from raw materials comprising the following weight percentages: Daliresen or its pharmaceutically acceptable salts, 3.2%–4.2%. Suspension agent 1.5%~2.5% Osmotic pressure regulator 2%~4% Solvent 2%~3% Surfactant 0.005%~0.01% The remainder is water.

[0026] In one embodiment, the nasal spray is made from raw materials comprising the following weight percentages: Daliresen or its pharmaceutically acceptable salts, 3.2%–4.0%. Suspension agent 1.5%~2.5% Osmotic pressure regulator 2%~4% Solvent 2%~3% Surfactant 0.005%~0.01% The remainder is water.

[0027] In one embodiment, the nasal spray further includes 0.01 wt% to 0.05 wt% of an antibacterial agent and 0.03 wt% to 0.05 wt% of a pH adjuster.

[0028] In one embodiment, the nasal spray further includes 0.01 wt% to 0.03 wt% of an antibacterial agent and 0.04 wt% to 0.05 wt% of a pH adjuster.

[0029] In one embodiment, the nasal spray is made from the following raw materials by weight percentage: Daliresen hydrochloride or its pharmaceutically acceptable salts, 3.5%–3.7%. Microcrystalline cellulose, sodium carboxymethyl cellulose co-treated product: 1.9%–2.1% Osmotic pressure regulator 2.9%~3.1% Solvent 2.4%~2.6% Surfactant 0.009%~0.01% pH adjuster 0.047%~0.049% Antibacterial agent 0.018%~0.022% The balance is water.

[0030] In one embodiment, the osmotic pressure regulator is one or more of sodium chloride, dextrose, mannitol, sorbitol.

[0031] In one embodiment, the surfactant is one or more of polysorbate 80, polysorbate 60, poloxamer 188, poloxamer 182, polyoxyl hydrogenated castor oil.

[0032] In one embodiment, the solvent is one or more of propylene glycol, glycerin, polyethylene glycol 200 (PEG-200), polyethylene glycol 400 (PEG-400).

[0033] In one embodiment, the pH regulator is one or more of citric acid, sodium citrate, sodium hydroxide, hydrochloric acid, disodium hydrogen phosphate.

[0034] In one embodiment, the bacteriostatic agent is one or more of benzalkonium chloride, phenoxyethanol, potassium sorbate.

[0035] In other embodiments of the present application, a method for preparing the above-mentioned nasal spray containing darinapragil is disclosed, comprising the following steps: (1) crushing darinapragil or its pharmaceutically acceptable salt; (2) adding the osmotic pressure regulator and the suspending agent to part of the water and dissolving; (3) adding the surfactant, the solvent and the crushed raw material of step (1) to the remaining water and homogeneously dispersing; (4) adding the solution of step (3) to the solution of step (2) and homogeneously stirring and dispersing to obtain the nasal spray.

[0036] In the following examples of the present application, all the excipients are of pharmaceutical grade or approved for use in nasal spray products, and are all from the market.

[0037] The present application will be described in detail below in combination with the accompanying drawings and specific examples.

[0038] Example 1 nasal sprays with different contents of darinapragil hydrochloride In this example, nasal sprays with different contents of darinapragil hydrochloride (3 wt%, 3.6 wt% and 4.2 wt%) were prepared, each with 166 μl per spray, and the formulations are shown in Table 1.

[0039]

[0040] The method for preparing the nasal spray comprises the following steps: 1. crushing darinapragil hydrochloride so that the D90 of the raw material is <5 μm.

[0041] 2. Add pH adjuster, osmotic pressure regulator, bacteriostatic agent, suspending agent into part of purified water, and dissolve completely.

[0042] 3. Add surfactant, solvent and crushed raw material into the rest of purified water, and homogenize and disperse.

[0043] 4. Add the solution of step 3 into the solution of step 2, and homogenize and disperse evenly, to obtain the nasal spray, with pH 5.8-6.2.

[0044] Example 2. Nasal spray of daliresp hydrochloride prepared with different suspending agents In this example, nasal sprays of daliresp hydrochloride with different kinds of suspending agents were prepared, with each spray of 166 μl, and the formulations are shown in Table 2.

[0045]

[0046] The nasal sprays were prepared according to the method of Example 1.

[0047] Example 3. Nasal sprays of daliresp hydrochloride with different amounts of suspending agent In this example, nasal sprays of daliresp hydrochloride with different amounts of suspending agent (1.5%, 2.5%) were prepared, with each spray of 166 μl, and the formulations are shown in Table 3.

[0048]

[0049] The nasal sprays were prepared according to the method of Example 1.

[0050] Example 4. Nasal sprays of daliresp hydrochloride with different amounts of surfactant In this example, nasal sprays of daliresp hydrochloride with different amounts of surfactant (0.005%) were prepared, with each spray of 166 μl, and the formulations are shown in Table 4.

[0051]

[0052] The nasal sprays were prepared according to the method of Example 1.

[0053] Example 5. Nasal sprays of daliresp hydrochloride with different formulations In this example, nasal sprays of daliresp hydrochloride with different formulations were prepared, with each spray of 166 μl, and the formulations are shown in Table 5.

[0054]

[0055] The nasal sprays were prepared according to the method of Example 1.

[0056] Preparation of nasal spray of different particle sizes of dalireline hydrochloride The nasal spray of different particle sizes of dalireline hydrochloride was prepared in this comparative example, and the formulation was shown in Table 6.

[0057]

[0058] The nasal spray was prepared according to the method of Example 1.

[0059] Preparation of nasal spray of different types of suspending agents The nasal spray of different types of suspending agents was prepared in this comparative example (other raw materials were the same as those of sample 2), and the formulation was shown in Table 7.

[0060]

[0061] The nasal spray was prepared according to the method of Example 1.

[0062] Test of performance of nasal spray of dalireline hydrochloride 1. Microscopic observation According to the first method of 0982 in the fourth part of the Chinese Pharmacopoeia (2025 edition), the raw material dalireline hydrochloride and the nasal spray of sample 2 were observed under a microscope at 500 times magnification. The results were shown in Figures 2-3 , and the results showed that the particle sizes of the API in the raw material and sample 2 solution were basically the same under microscopic observation.

[0063] 2. Sedimentation volume ratio According to the sedimentation volume ratio test method of 0123 in the fourth part of the Chinese Pharmacopoeia (2025 edition), the nasal sprays of samples 1-11, samples 14-15 were detected, and the results were shown in Table 8.

[0064]

[0065] The results in Table 8 showed that the sedimentation volume ratios of samples 1-11 were all more than 0.90, which met the standard. The sedimentation volume ratios of samples 14-15 were all less than 0.90, which did not meet the standard.

[0066] 3. Crystal form Raman scanning and XRD scanning were performed on the raw material dalireline hydrochloride and the nasal spray of sample 2, and the results were shown in Figures 4-6 and Figures 7-9 , and the results showed that the raw material in the nasal spray prepared by the application was consistent with the crystal form of the raw material, and no crystal transformation occurred.

[0067] 4. Dissolution rate The dissolution of samples 1-11 was detected by the second method of 0931 in the fourth part of the 2025 edition of the Chinese Pharmacopoeia, and the results are shown in Table 9.

[0068]

[0069] Table 9 shows that the 30 min dissolution of samples 1-11 and samples 14-15 is greater than 80%, while the 30 min dissolution of samples 12-13 is less than 80%. Therefore, the particle size of the raw material drug daliresp hydrochloride is too large, which can significantly affect the dissolution of the nasal spray.

[0070] 5. Delivery dose uniformity Samples 2, 7, 8, 14 and 15 were detected by the in-bottle delivery dose uniformity method of 0106 in the fourth part of the 2025 edition of the Chinese Pharmacopoeia, and the detection results are shown in Table 8.

[0071]

[0072] Table 10 shows that the delivery dose uniformity of the nasal spray of samples 2, 7 and 8 is qualified. The delivery uniformity of the nasal spray of samples 14-15 does not meet the standard of the 2025 edition of the Chinese Pharmacopoeia.

[0073] The technical features of the above-described embodiments can be combined in any manner. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described, but as long as the combinations of the technical features do not contradict, they should be considered within the scope of the present disclosure.

[0074] The above-described embodiments only express several embodiments of the present application, and the description is more specific and detailed, but it should not be understood as limiting the scope of the patent. It should be noted that for ordinary skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of the present application. Therefore, the scope of protection of the present application should be subject to the appended claims.

Claims

1. A nasal spray comprising daridorexant, characterized in that, It is made of raw materials including the following weight percentages: Darireresin or its pharmaceutically acceptable salt 3%~4.2% Suspending agent 1%~3% Osmotic pressure regulator 2%~6% Solvent 2%~5% Surface active agent 0.003%~0.012% The balance is water. The particle size D90 of the Darireresin or its pharmaceutically acceptable salt is <5 μm; the suspending agent is one or more of microcrystalline cellulose sodium carboxymethyl cellulose co-treatment, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, xanthan gum, carbomer, povidone.

2. The nasal spray containing daridorexant according to claim 1, wherein It is made of raw materials including the following weight percentages: Darireresin or its pharmaceutically acceptable salt 3.2%~4.2% Suspending agent 1.5%~2.5% Osmotic pressure regulator 2%~4% Solvent 2%~3% Surface active agent 0.005%~0.01% The balance is water.

3. The nasal spray containing daridorexant of claim 2, wherein, It is made of raw materials including the following weight percentages: Darireresin or its pharmaceutically acceptable salt 3.2%~4.0% Suspending agent 1.5%~2.5% Osmotic pressure regulator 2%~4% Solvent 2%~3% Surface active agent 0.005%~0.01% The balance is water.

4. The nasal spray containing daridorexant according to any one of claims 1-3, wherein, It also includes 0.01 wt%~0.05 wt% of bacteriostatic agent and 0.03 wt%~0.05 wt% of pH regulator.

5. The nasal spray containing daridorexant of claim 4, wherein, It also includes 0.01 wt%~0.03 wt% of bacteriostatic agent and 0.04 wt%~0.05 wt% of pH regulator.

6. The nasal spray containing daridorexant of claim 5, wherein, It is made of raw materials including the following weight percentages: Darireresin hydrochloride or its pharmaceutically acceptable salt 3.5%~3.7% Microcrystalline cellulose sodium carboxymethyl cellulose co-treatment 1.9%~2.1% Osmotic pressure regulator 2.9%~3.1% Solvent 2.4%~2.6% Surface active agent 0.009%~0.01% pH regulator 0.047%~0.049% Bacteriostatic agent 0.018%~0.022% The balance is water.

7. The nasal spray containing daridorexant of claim 6, wherein, The osmotic pressure regulator is one or more of sodium chloride, glucose, mannitol, sorbitol; And / or, the surface active agent is one or more of polysorbate 80, polysorbate 60, poloxamer 188, poloxamer 182, polyoxyethylene hydrogenated castor oil; And / or, the solvent is one or more of propylene glycol, glycerol, polyethylene glycol 200, polyethylene glycol 400; And / or, the pH regulator is one or more of citric acid, sodium citrate, sodium hydroxide, hydrochloric acid, disodium hydrogen phosphate; And / or, the bacteriostatic agent is one or more of benzalkonium chloride, phenoxyethanol, potassium sorbate.

8. A process for the preparation of a nasal spray containing daridorexant according to any one of claims 1 to 7, characterized in that, Including the following steps: (1) Darireresin or its pharmaceutically acceptable salt is crushed; (2) The osmotic pressure regulator, the suspending agent is added to part of the water, dissolved; (3) The surface active agent, the solvent and the raw material medicine after crushing in step (1) are added to the remaining water, homogenously dispersed; (4) The solution of step (3) is added to the solution of step (2), homogeneously stirred and dispersed, which is obtained.

9. The method of claim 8, wherein the nasal spray comprising daridorexant is prepared by, The Darireresin or its pharmaceutically acceptable salt is crushed in step (1) to make D90 <4 μm.

10. Use of a nasal spray containing daridorexant as defined in any one of claims 1 to 7 for the treatment of difficulty falling asleep and / or difficulty maintaining sleep.

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