Butylphthalide Oral Solution and Its Preparation Method and Application

Abstract

The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a butylphthalide oral solution. The oral solution contains butylphthalide, hydroxypropyl-β-cyclodextrin and water, and is characterized in that the oral solution further comprises citric acid and / or citrate, and the mass ratio of butylphthalide, hydroxypropyl-β-cyclodextrin and water is 1:18-25:50-150. The butylphthalide oral solution of the present invention has stable quality, is safe and reliable, and has almost no pungent and throat-irritating feeling, and can be taken orally or by nasogastric feeding, solving the clinical pain points.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and specifically relates to a butylphthalide oral solution and a preparation method and application thereof. Background Art

[0002] Butylphthalide (3-n-butylphthalide, referred to as NBP), chemical name 3-butyl-1 (H) -isobenzofuranone, also known as apigenin, can be extracted from celery seeds, can also be artificially synthesized. Butylphthalide is an oily liquid, insoluble in water, sensitive to light, with a strong celery smell, contains a chiral carbon atom in the molecule, so it has two optical isomers, namely levorotatory butylphthalide and dextrorotatory butylphthalide, and its drug form is usually levorotatory butylphthalide or racemic butylphthalide. Butylphthalide can reduce the infarct focus after focal cerebral ischemia, increase cerebral blood flow in the ischemic area and improve microcirculation in the ischemic area, protect mitochondrial function, reduce the degree of neurological damage, improve brain energy metabolism after global cerebral ischemia, etc., and act on multiple links of cerebral ischemia pathology; reported indications include mild, moderate and severe stroke, cerebral ischemia, cerebral infarction, dementia, anti-thrombosis, Parkinson's syndrome, etc.

[0003] The chemical structure of butylphthalide is as follows:

[0004]

[0005] For the above-mentioned cerebral ischemic diseases, especially moderate to severe stroke, cerebral ischemia, cerebral infarction, etc., it is very easy to cause patients to experience coma, impaired consciousness, paralysis, limb numbness and other symptoms, causing patients to have difficulty swallowing or unable to eat orally, so traditional conventional oral solid preparations such as tablets, capsules or oral lyophilized powders are no longer applicable; and infusion is inconvenient to use and takes time to reach the therapeutic dose, and is not suitable for sudden treatment. At present, some clinical practices are to disassemble the soft capsule and use a nasogastric tube to inject the liquid medicine in the capsule into the stomach for treatment; but the liquid medicine in the capsule is usually a viscous oily liquid with poor fluidity, resulting in huge deviations in the dosage, making it difficult to achieve the purpose of clinical treatment. For this reason, there is an urgent need for a liquid oral preparation of butylphthalide that is easy to swallow (including nasogastric feeding).

[0006] There are few reports on oral solutions of butylphthalide in the prior art. Currently, the only available one is a butylphthalide oral solution disclosed in patent CN109985035A, but its taste is extremely spicy and irritating to the throat, and its content in the disclosed 6-month stability data is reduced from 100% to 95.6%, and its stability is poor.

[0007] In view of this, how to provide a butylphthalide oral solution with good taste and stable and controllable quality is a difficult problem that needs to be solved urgently in clinical practice. Summary of the invention

[0008] In view of the problems existing in the prior art, the purpose of the present invention is to provide a butylphthalide oral solution with high concentration, small volume and simple preparation process. The butylphthalide oral solution of the present invention uses hydroxypropyl-β-cyclodextrin as a co-solvent and a complexation promoter, which can increase the complexation rate while significantly reducing the pungent and throat-irritating taste of butylphthalide, and has stable quality, and can meet the treatment needs of oral administration and nasal feeding at the same time.

[0009] The present invention provides a butylphthalide oral solution, which comprises butylphthalide, a co-solvent and water. The co-solvent is hydroxypropyl-β-cyclodextrin. The oral solution further comprises a complexation promoter, and the mass ratio of butylphthalide, hydroxypropyl-β-cyclodextrin and water is 1:18-25:50-150.

[0010] Further, the above complexation promoter is selected from citric acid and / or citrate.

[0011] Further, the mass ratio of citric acid and / or citrate to butylphthalide is 0.01-1.0:1; preferably, the mass ratio of citric acid and / or citrate to butylphthalide is 0.05-0.5:1.

[0012] Further, the above co-solvent further comprises sodium sulfobutyl ether β-cyclodextrin.

[0013] Furthermore, the above citrate is selected from sodium citrate, potassium citrate, magnesium citrate or ammonium citrate.

[0014] Further, the mass ratio of butylphthalide, hydroxypropyl-β-cyclodextrin and water in the above oral solution is 1:20-23:50-150.

[0015] Furthermore, the mass ratio of butylphthalide, hydroxypropyl-β-cyclodextrin and water in the above oral solution is 1:20-23:55-110.

[0016] Further, the pH value of the above oral solution is 3.5-5.5.

[0017] Furthermore, the pH value of the above oral solution is 4.0-5.0.

[0018] Further, the pH regulator of the above oral solution is selected from sodium acetate, acetic acid, glacial acetic acid, aspartic acid, benzenesulfonic acid, benzoic acid, sodium benzoate, sodium carbonate, citric acid, sodium citrate, glycine, glycine hydrochloride, hydrochloric acid, hydrobromic acid, lactic acid, sodium lactate, maleic acid, methanesulfonic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sulfuric acid, sodium hydroxide, tartaric acid or sodium tartrate.

[0019] Furthermore, the pH regulator of the above oral solution is selected from hydrochloric acid, sodium hydroxide, acetic acid or sodium dihydrogen phosphate.

[0020] Further, the above oral solution further comprises a flavoring agent.

[0021] Further, the above flavoring agent is selected from one or more of a salt flavoring agent, a sweetening agent, an aromatic agent, and an acid flavoring agent.

[0022] Still further, the above flavoring agent is selected from a salt flavoring agent, a sweetening agent, and an aromatic agent.

[0023] Further, the above salt flavoring agent, sweetening agent, aromatic agent, and acid flavoring agent refer to excipients included in the scope of pharmaceutical excipients in this field or pharmaceutical excipients widely used in this field.

[0024] Further, the above flavoring agent is selected from one or more of sodium chloride, potassium chloride, ammonium chloride, sodium malate, sucralose, stevioside, granulated sugar, sweet orange essence, apple essence, orange essence, banana essence, or lemon essence.

[0025] Still further, the above flavoring agent is selected from one or more of sodium chloride, sucralose, and sweet orange essence.

[0026] Further, the specification of the above oral solution is 2 to 15 ml; preferably, the specification of the above oral solution is 5 to 11 ml.

[0027] Further, the present invention provides a preparation method of the above oral solution, comprising the following steps:

[0028] (1) Weigh the prescribed amount of solubilizer and complexation promoter, add water accounting for 50 - 70% of the total volume at a temperature of 60 - 90 °C, stir until completely dissolved, then add the prescribed amount of butylphthalide, and stir at 60 - 90 °C for 80 - 120 min until completely dissolved, and then cool down to 20 - 35 °C;

[0029] (2) Make up the volume with water and stir evenly;

[0030] (3) Filter, fill, and sterilize.

[0031] Further, the preparation method of the above oral solution comprises the following steps:

[0032] (1) Weigh the prescribed amount of solubilizer and complexation promoter, add water accounting for 50 - 70% of the total volume at a temperature of 60 - 90 °C, stir until completely dissolved, then add the prescribed amount of butylphthalide, and stir at 60 - 90 °C for 80 - 120 min until completely dissolved, and then cool down to 20 - 35 °C;

[0033] (2) Make up the volume with water, and adjust the pH value of the solution to the target value with a pH regulator;

[0034] (3) Filter, fill, and sterilize.

[0035] Further, the preparation method of the above oral solution comprises the following steps:

[0036] (1) Weigh the prescribed amount of solubilizer and complexation promoter, add 50 - 70% of the total volume of water at a temperature of 60 - 90°C, stir until completely dissolved, then add the prescribed amount of butylphthalide, and stir at 60 - 90°C for 80 - 120 min until completely dissolved, and then cool down to 20 - 35°C;

[0037] (2) Weigh the prescribed amount of flavoring agent, add 2 - 5% of the total volume of water and stir until dissolved, then add it to the solution in step (1), stir and mix evenly, make up the volume with water, and adjust the pH value of the solution to the target value with a pH regulator;

[0038] (3) Filter, fill, and sterilize.

[0039] Furthermore, the solubilizer in the above step (1) is hydroxypropyl - β - cyclodextrin, and the complexation promoter is citric acid and / or citrate.

[0040] Furthermore, the filtration in the above step (3) is filtration through a 0.22 - 0.85 μm filter membrane, and the sterilization condition is sterilization at 121°C for 5 - 20 min.

[0041] Furthermore, the above oral solution is for oral administration or nasal feeding.

[0042] The above "butylphthalide" includes but is not limited to racemic butylphthalide and levobutylphthalide. In a specific prescription, the mass of butylphthalide is calculated based on C 12 H 14 O2.

[0043] The above water includes but is not limited to purified water, ultrapure water, and distilled water.

[0044] The containers of the above butylphthalide oral solution include but are not limited to sodium - calcium glass - controlled oral liquid bottles, low - borosilicate glass - controlled oral liquid bottles, medium - borosilicate glass - controlled oral liquid bottles, oral liquid medicinal polyester bottles, oral liquid medicinal polypropylene bottles, oral liquid medicinal high - density polyethylene bottles, etc. The containers of the above butylphthalide oral solution are colorless or brown.

[0045] In the present invention, "above" or "below" both include the present number.

[0046] Beneficial effects : The butylphthalide oral solution of the present invention uses citric acid and / or citrate as the complexation promoter, unexpectedly improving the inclusion integrity and inclusion stability of butylphthalide, successfully masking the pungent and throat - irritating taste of butylphthalide itself, making the taste of this product completely without or almost without pungent and throat - irritating feeling, and having stable quality. Especially in the 30 - day light - influencing factor test, the oral solution is colorless and clear, the maximum single impurity does not exceed 0.05%, the total impurity does not exceed 0.07%, and there are no visible foreign matters to the naked eye. The quality is safe and controllable, meeting the medicinal - grade quality standard. Detailed implementation manners

[0047] The solutions of the present invention will be explained below in conjunction with examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For specific technologies or conditions not specified in the examples, they shall be carried out according to the technologies or conditions described in the literature in the field or according to the product specifications. For reagents or instruments without indicating the manufacturer, they are all conventional products obtained through commercial purchase.

[0048] Comparative Example 1: Butylphthalide oral solution and its preparation

[0049] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 15.6g 15.6 Purified water (volume made up to) 50 ml (10 vials) 50

[0050] Preparation process: Weigh the prescribed amount of hydroxypropyl-β-cyclodextrin, add purified water at 70 - 80°C accounting for 65% of the total volume, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 70 - 80°C for 120 min, cool the solution to 25 - 30°C after complete dissolution; make up the volume with purified water; filter through a 0.8 μm filter membrane, fill into 10 equal portions (5 ml / portion); sterilize at 121°C for 15 min.

[0051] Comparative Example 2: Butylphthalide oral solution and its preparation

[0052] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 15.6g 15.6 Sorbitol solution (70%) 5g / Potassium sorbate 75 mg / Purified water (volume made up to) 50 ml (10 vials) 50

[0053] Preparation process: Weigh the prescribed amount of hydroxypropyl-β-cyclodextrin, sorbitol solution (70%), and potassium sorbate, add purified water at 70 - 80°C accounting for 65% of the total volume, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 70 - 80°C for 120 min, cool the solution to 25 - 30°C after complete dissolution; make up the volume with purified water; filter through a 0.8 μm filter membrane, fill into 10 equal portions; sterilize at 121°C for 15 min.

[0054] Comparative Example 3: Butylphthalide oral solution and its preparation

[0055] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 18g 18 Sodium oleate 0.5g / Purified water (volume made up to) 50 ml (10 vials) 50

[0056] Preparation process: The same as Comparative Example 2.

[0057] Comparative Example 4: Butylphthalide oral solution and its preparation

[0058] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 36g 36 Purified water (volume made up to) 50 ml (10 vials) 50

[0059] Preparation process: The same as Comparative Example 1. The solution could not be completely dissolved.

[0060] Comparative Example 5: Butylphthalide oral solution and its preparation

[0061] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 36g 36 Sodium citrate 1g / Purified water (volume made up to) 50 ml (10 vials) 50

[0062] Preparation process: same as Comparative Example 2. The solution could not be completely dissolved.

[0063] Comparative Example 6: Butylphthalide Oral Solution and Its Preparation

[0064] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 36g 36 Sodium citrate 1g / Purified water (volume made up to) 50 ml (10 vials) 50 Solution pH value pH 4.5 /

[0065] Preparation process: same as Comparative Example 2. The solution could not be completely dissolved.

[0066] Example 1: Butylphthalide Oral Solution and Its Preparation

[0067] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 18g 18 Sodium citrate 0.05g / Purified water (volume made up to) 50 ml (10 vials) 50

[0068] Preparation process: Weigh the prescribed amount of hydroxypropyl-β-cyclodextrin and sodium citrate, add 65% of the total volume of purified water at a temperature of 70 - 80°C, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 70 - 80°C for 120 min. After the solution is completely dissolved, cool it to 25 - 30°C; make up the volume with purified water; filter through a 0.8 μm filter membrane, and fill it evenly into 10 vials; sterilize at 121°C for 15 min.

[0069] Example 2: Butylphthalide Oral Solution and Its Preparation

[0070] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 25g 25 Sodium citrate 0.5g / Purified water (volume made up to) 150 ml (10 vials) 150

[0071] Preparation process: same as Example 1.

[0072] Example 3: Butylphthalide Oral Solution and Its Preparation

[0073] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 20g 20 Sodium citrate 1g / Purified water (volume made up to) 150 ml (10 vials) 150

[0074] Preparation process: same as Example 1.

[0075] Example 4: Butylphthalide Oral Solution and Its Preparation

[0076] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 23g 23 Sodium citrate 0.01g / Purified water (volume made up to) 50 ml (10 vials) 50

[0077] Preparation process: same as Example 1.

[0078] Example 5: Butylphthalide Oral Solution and Its Preparation

[0079] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 22g 22 Citric acid 0.060g / Sodium citrate 0.078g Purified water (volume made up to) 55 ml (10 vials) 55

[0080] Preparation process: Weigh the prescribed amounts of hydroxypropyl-β-cyclodextrin, citric acid, and sodium citrate, add 65% of the total volume of purified water at a temperature of 60 - 70°C, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 70 - 80°C for 90 min, cool to 20 - 25°C after the solution is completely dissolved; make up the volume with purified water; filter through a 0.45 μm filter membrane, and fill into 10 vials evenly; sterilize at 121°C for 10 min.

[0081] Example 6: Butylphthalide Oral Solution and Its Preparation

[0082] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 25g 25 Citric acid 1g / Purified water (volume made up to) 150 ml (10 vials) 150

[0083] Preparation process: The same as in Example 1.

[0084] Example 7: Butylphthalide Oral Solution and Its Preparation

[0085] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 18g 18 Citric acid 0.01g / Purified water (volume made up to) 55 ml (10 vials) 55

[0086] Preparation process: The same as in Example 1.

[0087] Example 8: Butylphthalide Oral Solution and Its Preparation

[0088] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 18g 18 Citric acid 0.01g / Solution pH value 5.5 / Purified water (volume made up to) 150 ml (10 vials) 150

[0089] Preparation process: Weigh the prescribed amounts of hydroxypropyl-β-cyclodextrin and citric acid, add 60% of the total volume of purified water at a temperature of 75 - 80°C, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 75 - 80°C for 90 min, cool to 25 - 30°C after the solution is completely dissolved; make up the volume with purified water, adjust the pH of the solution to the target value with 10% (w / v) citric acid or 10% (w / v) sodium citrate; filter through a 0.8 μm filter membrane, and fill into 10 vials evenly; sterilize at 121°C for 15 min.

[0090] Example 9: Butylphthalide Oral Solution and Its Preparation

[0091] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 25g 25 Citric acid 1g / Solution pH value 3.5 / Purified water (volume made up to) 50 ml (10 vials) 50

[0092] Preparation process: The same as in Example 8.

[0093] Example 10: Butylphthalide Oral Solution and Its Preparation

[0094] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 20g 20 Citric acid 0.05g / Solution pH value 4.0 / Purified water (volume made up to) 50 ml (10 vials) 50

[0095] Preparation process: The same as in Example 8.

[0096] Example 11: Butylphthalide Oral Solution and Its Preparation

[0097] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 23g 23 Citric acid 0.5g / Solution pH value 5.0 / Purified water (volume made up to) 150 ml (10 vials) 150

[0098] Preparation process: the same as that of Example 8.

[0099] Example 12: Butylphthalide Oral Solution and Its Preparation

[0100] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 20g 20 Citric acid 0.1g / Solution pH value 4.5 / Purified water (volume made up to) 100 ml (10 vials) 100

[0101] Preparation process: the same as that of Example 8.

[0102] Example 13: Butylphthalide Oral Solution and Its Preparation

[0103] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 23g 23 Sodium citrate 1g / Solution pH value 5.0 / Purified water (volume made up to) 150 ml (10 vials) 150

[0104] Preparation process: the same as that of Example 8.

[0105] Example 14: Butylphthalide Oral Solution and Its Preparation

[0106] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 18g 18 Sodium citrate 0.01g / Solution pH value 4.0 / Purified water (volume made up to) 55 ml (10 vials) 55

[0107] Preparation process: the same as that of Example 8.

[0108] Example 15: Butylphthalide Oral Solution and Its Preparation

[0109] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 22g 22 Citric acid 0.060g Sodium citrate 0.078g / Solution pH value 4.5 / Purified water (volume made up to) 55 ml (10 vials) 55

[0110] Preparation process: the same as that of Example 8.

[0111] Example 16: Butylphthalide Oral Solution and Its Preparation

[0112] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 18g 18 Citric acid 0.1g / Solution pH value 3.5 / Purified water (volume made up to) 150 ml (10 vials) 150

[0113] Preparation process: Weigh the prescription amount of hydroxypropyl-β-cyclodextrin and citric acid, add 60% of the total volume of purified water at 70 - 80°C, stir until completely dissolved, then add the prescription amount of butylphthalide, stir at 70 - 80°C for 90 minutes. After the solution is completely dissolved, cool it to 20 - 25°C; make up the volume with purified water, adjust the pH of the solution to the target value with 1mol / L potassium dihydrogen phosphate solution; filter through a 0.8μm filter membrane, and fill it evenly into 10 vials; sterilize at 121°C for 15 minutes.

[0114] Example 17: Butylphthalide Oral Solution and Its Preparation

[0115] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 23g 23 Sodium citrate 0.1g / Solution pH value 5.0 / Purified water (volume made up to) 55 ml (10 vials) 55

[0116] Preparation process: Weigh the prescribed amount of hydroxypropyl-β-cyclodextrin and sodium citrate, add 60% of the total volume of purified water at a temperature of 75 - 80°C, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 75 - 80°C for 90 minutes. After the solution is completely dissolved, cool it to 25 - 30°C; make up the volume with purified water, adjust the pH of the solution to the target value with 10% (w / v) citric acid or 10% (w / v) sodium citrate; filter through a 0.8μm filter membrane, and fill into 10 vials evenly; sterilize at 121°C for 15 minutes.

[0117] Example 18: Butylphthalide Oral Solution and Its Preparation

[0118] Material Prescription quantity Mass ratio Butylphthalide 1g 1 Hydroxypropyl-β-cyclodextrin 23g 23 Citric acid 0.02g / Sodium citrate 0.01g / Sodium chloride 0.51g / Sucralose 0.28g / Sweet orange essence 0.04g / Solution pH value 4.5 / Purified water (volume made up to) 55 ml (10 vials) 55

[0119] Preparation process: Weigh the prescribed amount of cosolvent and complexation promoter (citric acid, sodium citrate), add 50 - 60% of the total volume of purified water at a temperature of 80 - 90°C, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 80 - 90°C for 80 - 90 minutes until completely dissolved, and then cool it to 25 - 30°C; weigh the prescribed amount of flavoring agent, add 4% of the total volume of purified water and stir to dissolve, then add it to the above-mentioned medicinal liquid, stir and mix evenly, make up the volume with purified water, adjust the pH value of the solution to the target value with 10% (w / v) citric acid or 10% (w / v) sodium citrate; filter through a 0.8μm filter membrane, fill into 10 vials evenly, and sterilize at 121°C for 20 minutes.

[0120] Test Example 1 Taste Evaluation

[0121] 1. Samples: Comparative Examples 1 - 3, Examples 1 - 18.

[0122] 2. Method: Take the above samples for manual tasting, score according to the degree of pungency and throat irritation, with the score ranging from 0 - 10 points; no pungency or almost no pungency is 8 - 10 points, strong pungency or intolerable pungency is 0 - 4 points, and the taste between the two is scored 5 - 7 points according to personal feelings. Finally, calculate the average score of each sample. Samples with a score of 8 - 10 are finally evaluated as Grade A, 5 - 7 as Grade B, and 0 - 4 as Grade C.

[0123] 3. Results: The taste grades of each sample are as shown in Table 1 below:

[0124] Table 1

[0125] Sample Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 1 Example 2 Example 3 Example 4 Taste C B C A A A A Sample Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Taste A A A A A A A Sample Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Taste A A A A A A A

[0126] The above table shows that although hydroxypropyl-β-cyclodextrin has a strong solubilizing effect on butylphthalide, it cannot mask the taste of butylphthalide, and has a strong pungent and throat-irritating feeling (Comparative Example 1). Moreover, whether increasing the dosage of the solubilizer (Comparative Example 3), using the excipients disclosed in the prior art (Comparative Example 2), or other stabilizers (Comparative Example 3), it is impossible or very difficult to improve / mask the pungent and throat-irritating feeling of the butylphthalide oral solution. However, unexpectedly, the inventors of the present application found that when citric acid and / or citrate (sodium) (Examples 1 to 7) are used, the taste of the butylphthalide oral solution can be significantly improved. Especially when the pH value of the butylphthalide oral solution is controlled to be 3.5 to 5.5, especially 4.0 to 5.0, there will be a slightly sweet aftertaste after the oral solution enters the throat.

[0127] Thus, it can be seen that the butylphthalide of the present invention has a good inclusion rate and inclusion stability, has no or basically no pungent and throat-irritating taste, and improves the oral compliance of the butylphthalide oral solution.

[0128] Test Example 2 Investigation of Light Stability

[0129] Samples of Comparative Examples 1 to 3 and Examples 1 to 18 were taken for investigation of the light influence factors (illuminance is 45001x ± 5001x, and the total illuminance of the light source should not be less than 1.2X106 luX*hr, and the energy of the near-ultraviolet lamp is not less than 200W*hr / m2) for 30 days, and samples were taken for detection at 0 day, 10 days, and 30 days respectively.

[0130] Detection method for related substances: The method of Example 2 of Patent CN201910466351.4 was adopted.

[0131] Content detection method: (1) Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the filler; 10 mmol / L potassium dihydrogen phosphate solution (adjusted to pH 3.0 with phosphoric acid)-acetonitrile (40:60) was used as the mobile phase; the detection wavelength was 230 nm; the injection volume was 5 μl. (2) Determination method: The labeled amount of butylphthalide (C 12 H 14 O2) was calculated by the external standard method based on the peak area.

[0132] Visible foreign matters: Determined according to the visible foreign matter inspection method in the General Principles of the Chinese Pharmacopoeia (2020 Edition), Method 1 (lamp inspection method). 0 visible foreign matters is grade A, 1 to 5 visible foreign matters is grade B, both meeting the standards; more than 6 visible foreign matters is grade C.

[0133] The light stability results of each sample at 0 day and 30 days are statistically shown in Table 2 below:

[0134] Table 2 Investigation results of the light stability of each sample

[0135]

[0136]

[0137] Note: “—” indicates that this item was not detected.

[0138] The above table shows that compared with Comparative Examples 1-3, the quality of the butylphthalide oral solution of the present invention remains stable after the 30-day light influence factor test. Among them, the appearance is colorless and clear, the pH value of the solution is stable (if any), the maximum single impurity does not exceed 0.05%, the total impurity does not exceed 0.07%, and the content remains basically unchanged; there is no or basically no visible foreign matter to the naked eye.

[0139] Therefore, it can be seen that the butylphthalide oral solution of the present invention has stable quality, is safe and controllable.

Claims

1. A butylphthalide oral solution, comprising butylphthalide, a solubilizer and water, wherein the solubilizer is hydroxypropyl-β-cyclodextrin, characterized in that The oral solution further contains an inclusion promoter, and the mass ratio of butylphthalide, hydroxypropyl-β-cyclodextrin and water is 1:18-25:50-150; the inclusion promoter is selected from citric acid and / or citrate; the pH value of the oral solution is 3.5-5.5, and the pH regulator is selected from citric acid or sodium citrate.

2. The oral solution according to claim 1, wherein The mass ratio of butylphthalide, hydroxypropyl-β-cyclodextrin and water is 1:20-23:50-150.

3. The oral solution according to claim 1, wherein The mass ratio of butylphthalide, hydroxypropyl-β-cyclodextrin and water is 1:20-23:55-110.

4. The oral solution according to claim 1, characterized in that, The pH value of the oral solution is 4.0-5.

0.

5. The oral solution according to claim 1, wherein, The oral solution further includes a flavoring agent.

6. The oral solution according to claim 5, characterized in that, The flavoring agent is selected from one or more of sodium chloride, potassium chloride, ammonium chloride, sodium malate, sucralose, stevioside, granulated sugar, sweet orange essence, apple essence, orange essence, banana essence or lemon essence.

7. The oral solution according to claim 1, wherein The specification of the oral solution is 2-15 ml.

8. The oral solution according to claim 7, wherein The specification of the oral solution is 5-11 ml.

9. The preparation method of the oral solution according to any one of claims 1 to 4, comprising the following steps: (1) Weigh the prescription amount of solubilizer and inclusion promoter, add 50-70% of the total volume of water at a temperature of 60-90 °C, stir until completely dissolved, then add the prescription amount of butylphthalide, and stir at 60-90 °C for 70-120 min until completely dissolved, and then cool down to 20-35 °C; (2) Make up the volume with water, and adjust the pH value of the solution to the target value with a pH regulator; (3) Filter, fill and sterilize.

10. The preparation method of the oral solution according to claim 5 or 6, comprising the following steps: (1) Weigh the prescription amount of solubilizer and inclusion promoter, add 50-70% of the total volume of water at a temperature of 60-90 °C, stir until completely dissolved, then add the prescription amount of butylphthalide, and stir at 60-90 °C for 70-120 min until completely dissolved, and then cool down to 20-35 °C; Weigh the prescription amount of flavoring agent, add 4% of the total volume of water and stir to dissolve, then add it to the above-mentioned medicinal liquid and stir evenly; (2) Make up the volume with water, and adjust the pH value of the solution to the target value with a pH regulator; (3) Filter, fill and sterilize.

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