Stable butylphthalide oral solution as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a butylphthalide oral solution as well as a preparation method and application thereof. The present invention provides an oral solution comprising a therapeutically effective amount of butylphthalide and pharmaceutically acceptable excipients, the therapeutically effective amount being a single daily dose, the single daily dose reaching an average Cmax of from 1.2 ng / ml to 3.2 ng / ml for every 1 mg of butylphthalide after administration to a human subject, the single daily dose being 120 mg-160 mg. The butylphthalide oral solution disclosed by the invention is stable in curative effect and suitable for treating cerebral ischemic diseases including mild, moderate and severe acute ischemic cerebral apoplexy and the like.

Description

Technical Field

[0001] The invention belongs to the technical 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), the chemical name is 3-butyl-1 (H) -isobenzofuranone, the chemical structure is as follows: .

[0003] The prior art reports of butylphthalide have multiple confirmed uses, such as the treatment and / or prevention of cerebral ischemic diseases, kidney disease, etc.; kidney disease includes acute or chronic renal insufficiency, stroke with renal insufficiency, renal failure, etc., and cerebral ischemic diseases include ischemic stroke, exemplified by but not limited to mild, moderate, and severe acute ischemic stroke, etc. Especially for moderate to severe acute cerebral ischemic diseases, patients are very likely 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orally, so traditional conventional oral solid preparations such as tablets, capsules or oral lyophilized powders are no longer applicable. At present, the only oral preparation of butylphthalide on the market in my country is CSPC Pharmaceutical Group's butylphthalide soft capsule (Enbipu®), which has a single-dose specification of up to 200 mg, a low blood drug concentration Cmax in the human body, and a maximum blood drug peak time Tmax of about 1.5 hours. Therefore, the soft capsule cannot meet the treatment needs of this type of disease from the perspective of patient compliance or emergency treatment effect. Therefore, the development of a liquid preparation of butylphthalide oral solution with good compliance, rapid onset and better efficacy meets the urgent need to solve clinical pain points.

[0004] In addition, since butylphthalide is insoluble in water, the primary consideration when preparing butylphthalide liquid preparations is the choice of solubilizer. Although the prior art discusses the solubilizing ability of a large number of cyclodextrins and their derivatives, the solubilizing effects of hydroxypropyl-β-cyclodextrin and sulfobutyl beta-cyclodextrin sodium have attracted great attention in the field, and the butylphthalide sodium chloride injection launched by Shijiazhuang Pharmaceutical Group has also proved the safety of hydroxypropyl-β-cyclodextrin. However, the prior art does not record any research on whether the butylphthalide-cyclodextrin inclusion complex formed by the inclusion of butylphthalide by such cyclodextrin derivatives has the effect of stably releasing butylphthalide, and the stable release of butylphthalide is crucial for the treatment of the above-mentioned diseases, especially the treatment of moderate to severe acute ischemic stroke.

[0005] Therefore, developing an oral solution of butylphthalide that is not only easy to take, fast in effect, and has significant and sustained efficacy, and improving the reliability of butylphthalide in treating special conditions of diseases in this field, is the key to ensuring the clinical efficacy of butylphthalide. Summary of the invention

[0006] In order to solve the problems existing in the prior art, the present invention provides a butylphthalide oral solution, and by controlling the dosage and particle size, a butylphthalide oral solution with rapid onset, significant therapeutic effect and sustained and stable therapeutic effect is provided.

[0007] The present invention provides a use of butylphthalide in preparing an oral solution preparation for treating and / or preventing ischemic stroke. The oral solution comprises a therapeutically effective amount of butylphthalide and a pharmaceutically acceptable excipient. The therapeutically effective amount is a single daily dose. After administration to human subjects, for each 1 mg of butylphthalide, the single daily dose reaches an average Cmax from 1.2 ng / ml to 3.2 ng / ml, and the single daily dose is 120 mg to 160 mg.

[0008] Furthermore, the above single daily dose is 125 mg to 160 mg.

[0009] Further, after administration to human subjects, the above single daily doses achieved average Cmax ranging from 1.7 ng / ml to 3.2 ng / ml for each 1 mg of butylphthalide.

[0010] Further, after administration to human subjects, for each 1 mg of butylphthalide, the above single daily dose achieves an average Cmax of from 1.5 ng / ml to 2.6 ng / ml; preferably an average Cmax of from 2.2 ng / ml to 2.6 ng / ml.

[0011] Furthermore, the above-mentioned ischemic stroke includes mild, moderate and severe acute ischemic stroke.

[0012] Furthermore, the above-mentioned butylphthalide is an inclusion compound of cyclodextrin or its derivatives, and the particle size of the inclusion compound is 1nm~8nm, preferably 3nm~6nm.

[0013] Furthermore, the intensity peak area of ​​the above inclusion compound particle size is not less than 90%, preferably not less than 95%.

[0014] Furthermore, the cyclodextrin or its derivative is hydroxypropyl-β-cyclodextrin, and the mass ratio of butylphthalide to hydroxypropyl-β-cyclodextrin is 1:19-25, preferably 1:20-24.

[0015] Furthermore, the pharmaceutically acceptable excipients are inclusion excipients, and the inclusion excipients include inorganic salts and acidifiers.

[0016] Furthermore, the above-mentioned inorganic salt includes sodium chloride, potassium chloride, lithium chloride, magnesium chloride, ammonium chloride, aluminum chloride, ferrous chloride, ferric chloride, sodium sulfate, magnesium sulfate, ammonium sulfate, sodium carbonate or sodium polyphosphate.

[0017] Furthermore, the acidifier comprises hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, glacial acetic acid or a buffer.

[0018] Further, the above buffer pair comprises citric acid and citrate, citric acid and phosphate, lactic acid and lactate, phosphoric acid and phosphate, acetic acid and acetate, or tartaric acid and tartrate. Exemplary include but are not limited to citric acid-sodium citrate, citric acid-potassium citrate, citric acid-disodium citrate, citric acid-trisodium citrate, citric acid-disodium hydrogen phosphate, lactic acid-sodium lactate, phosphoric acid-sodium dihydrogen phosphate, phosphoric acid-disodium hydrogen phosphate, acetic acid-sodium acetate, or tartaric acid-sodium tartrate.

[0019] Furthermore, the mass ratio of the inorganic salt to butylphthalide is 0.05-1.0:1, preferably 0.2-0.7:1.

[0020] Furthermore, the mass ratio of the acidifier to butylphthalide is 0.01-0.15:1.

[0021] Furthermore, the pH value of the oral solution is 3.5-5.5, preferably 4.0-5.0.

[0022] Furthermore, the oral solution also includes a flavoring agent; the flavoring agent includes one or more of a sweetener, a flavoring agent, a sour agent, and a salting agent.

[0023] Furthermore, the above-mentioned sweetener includes sucralose, glucose, white sugar, steviol glycoside, acesulfame potassium, xylitol or aspartame; the above-mentioned flavor includes sweet orange flavor, apple flavor, orange flavor, banana flavor or lemon flavor.

[0024] Furthermore, the preparation method of the above-mentioned oral solution includes the following steps: taking 50%~80% of the prescribed amount of water and heating it to 75℃~90℃, adding the prescribed amount of cyclodextrin or its derivatives and pharmaceutically acceptable excipients at one time or in batches while stirring, stirring to completely dissolve, adding butylphthalide, stirring at 65~90℃ for more than 90~150 minutes, cooling to obtain an inclusion complex solution, adding water to make up the full volume, stirring and mixing, adjusting the solution pH to the target value, filtering, filling, and sterilizing.

[0025] Preferably, the preparation method of the above-mentioned oral solution comprises the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75°C to 90°C, stirring and adding the prescribed amount of cyclodextrin or its derivatives to completely dissolve it, adding pharmaceutically acceptable excipients, stirring to completely dissolve it, adding butylphthalide, stirring at 65 to 90°C for more than 90 to 150 minutes, cooling to obtain an inclusion complex solution, adding water to make up to the full volume, stirring and mixing, adjusting the pH of the solution to the target value, filtering, filling, and sterilizing.

[0026] Furthermore, the preparation method of the above-mentioned oral solution includes the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75°C to 90°C, adding the prescribed amount of cyclodextrin or its derivatives and pharmaceutically acceptable excipients at one time or in batches while stirring, stirring to completely dissolve, adding butylphthalide, stirring at 65 to 90°C for more than 90 to 150 minutes, cooling to obtain an inclusion compound solution; taking another 10% of water that does not exceed the prescribed amount, adding a flavoring agent, adding it to the inclusion compound solution after all of it is dissolved, adding water to the full volume, stirring to mix, adjusting the solution pH to the target value, filtering, filling, and sterilizing.

[0027] Preferably, the preparation method of the above-mentioned oral solution comprises the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75°C to 90°C, stirring and adding the prescribed amount of cyclodextrin or its derivatives to completely dissolve, adding pharmaceutically acceptable excipients, stirring to completely dissolve, adding butylphthalide, stirring at 65 to 90°C for more than 90 to 150 minutes, and cooling to obtain an inclusion compound solution; taking another 10% of water not exceeding the prescribed amount, adding a flavoring agent, adding it to the inclusion compound solution after all the water is dissolved, adding water to the full volume, stirring and mixing, adjusting the pH of the solution to the target value, filtering, filling, and sterilizing.

[0028] Further, the above therapeutically effective amount is a single 120 mg daily dose, and wherein the single daily dose achieves a mean Cmax within the range of 80% to 125% of 175 ng / ml.

[0029] Further, the above therapeutically effective amount is a single 125 mg daily dose, and wherein the single daily dose achieves a mean Cmax within the range of 80% to 125% of 272 ng / ml.

[0030] Further, the above therapeutically effective amount is a single 136 mg daily dose, and wherein the single daily dose achieves a mean Cmax within the range of 80% to 125% of 304 ng / ml.

[0031] Further, the above therapeutically effective amount is a single 160 mg daily dose, and wherein the single daily dose achieves a mean Cmax within the range of 80% to 125% of 410 ng / ml.

[0032] Further, the above therapeutically effective amount is a single 120 mg daily dose, and wherein the single daily dose achieves an average AUC (0-24h) or average AUC (0-t) within the range of 80% to 125% of 308h*ng / ml.

[0033] Further, the above therapeutically effective amount is a single daily dose of 125 mg, and wherein the single daily dose achieves an average AUC (0-24h) or average AUC (0-t) within the range of 80% to 125% of 310 h*ng / ml.

[0034] Further, the above therapeutically effective amount is a single daily dose of 136 mg, and wherein the single daily dose achieves an average AUC (0-24h) or average AUC (0-t) within the range of 80% to 125% of 332h*ng / ml.

[0035] Further, the above therapeutically effective amount is a single 160 mg daily dose, and wherein the single daily dose achieves an average AUC (0-24h) or average AUC (0-t) within the range of 80% to 125% of 478h*ng / ml.

[0036] Further, the above therapeutically effective amount is a single 120 mg daily dose, and wherein the single daily dose achieves an average AUC (0-inf) within the range of 80% to 125% of 338 h*ng / ml.

[0037] Further, the above therapeutically effective amount is a single 125 mg daily dose, and wherein the single daily dose achieves an average AUC (0-inf) within the range of 80% to 125% of 340 h*ng / ml.

[0038] Further, the above therapeutically effective amount is a single 136 mg daily dose, and wherein the single daily dose achieves an average AUC (0-inf) within the range of 80% to 125% of 367 h*ng / ml.

[0039] Further, the above therapeutically effective amount is a single 160 mg daily dose, and wherein the single daily dose achieves an average AUC (0-inf) within the range of 80% to 125% of 514h*ng / ml.

[0040] The present invention also provides a butylphthalide oral solution for preparing a disease treatment and / or prevention, the oral solution comprising a therapeutically effective amount of butylphthalide and a pharmaceutically acceptable auxiliary material, the butylphthalide is an inclusion compound of cyclodextrin or its derivatives, the inclusion compound particle size is 1nm~8nm, and the specification of butylphthalide is 120mg~160mg.

[0041] Furthermore, the specification of the above-mentioned butylphthalide is 125~160mg.

[0042] Furthermore, the intensity peak area of ​​the above inclusion compound particle size is not less than 90%, preferably not less than 95%.

[0043] Furthermore, the particle size of the inclusion compound is 3nm~6nm.

[0044] Furthermore, the cyclodextrin or its derivative is hydroxypropyl-β-cyclodextrin, and the mass ratio of butylphthalide to hydroxypropyl-β-cyclodextrin is 1:19-25, preferably 1:20-24.

[0045] Furthermore, the pharmaceutically acceptable excipients are inclusion excipients, and the inclusion excipients include inorganic salts and acidifiers.

[0046] Furthermore, the above-mentioned inorganic salt includes sodium chloride, potassium chloride, lithium chloride, magnesium chloride, ammonium chloride, aluminum chloride, ferrous chloride, ferric chloride, sodium sulfate, magnesium sulfate, ammonium sulfate, sodium carbonate or sodium polyphosphate.

[0047] Furthermore, the above-mentioned acidifier comprises hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, glacial acetic acid or a buffer.

[0048] Further, the above buffer pair comprises citric acid and citrate, citric acid and phosphate, lactic acid and lactate, phosphoric acid and phosphate, acetic acid and acetate, or tartaric acid and tartrate. Exemplary include but are not limited to citric acid-sodium citrate, citric acid-potassium citrate, citric acid-disodium citrate, citric acid-trisodium citrate, citric acid-disodium hydrogen phosphate, lactic acid-sodium lactate, phosphoric acid-sodium dihydrogen phosphate, phosphoric acid-disodium hydrogen phosphate, acetic acid-sodium acetate, or tartaric acid-sodium tartrate.

[0049] Furthermore, the mass ratio of the inorganic salt to butylphthalide is 0.05-1.0:1, preferably 0.2-0.7:1.

[0050] Furthermore, the mass ratio of the above-mentioned acidifier to butylphthalide is 0.01~0.15:1.

[0051] Furthermore, the pH value of the oral solution is 3.5-5.5, preferably 4.0-5.0.

[0052] Furthermore, the oral solution also includes a flavoring agent; the flavoring agent includes one or more of a sweetener, a flavoring agent, a sour agent, and a salting agent.

[0053] Furthermore, the above-mentioned sweeteners include sucralose, glucose, white sugar, steviol glycosides, acesulfame potassium, xylitol, sucrose, fructose, oligofructose, maltose, starch sugar, lactose, saccharin or aspartame; the above-mentioned flavors include sweet orange flavor, apple flavor, orange flavor, banana flavor or lemon flavor.

[0054] Furthermore, the preparation method of the above-mentioned oral solution comprises the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75°C to 90°C, adding the prescribed amount of cyclodextrin or its derivatives and pharmaceutically acceptable excipients at one time or in batches while stirring, stirring to completely dissolve, adding butylphthalide, stirring at 65 to 90°C for more than 90 to 150 minutes, cooling to obtain an inclusion complex solution, adding water to make up the full volume, stirring and mixing, adjusting the solution pH to the target value, filtering, filling, and sterilizing.

[0055] Preferably, the preparation method of the above-mentioned oral solution comprises the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75°C to 90°C, stirring and adding the prescribed amount of cyclodextrin or its derivatives to completely dissolve it, adding pharmaceutically acceptable excipients, stirring to completely dissolve it, adding butylphthalide, stirring at 65 to 90°C for more than 90 to 150 minutes, cooling to room temperature to obtain an inclusion complex solution, adding water to make up to the full volume, stirring and mixing, adjusting the pH of the solution to the target value, filtering, filling, and sterilizing.

[0056] Furthermore, the preparation method of the above-mentioned oral solution includes the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75°C to 90°C, adding the prescribed amount of cyclodextrin or its derivatives and pharmaceutically acceptable excipients at one time or in batches while stirring, stirring to completely dissolve, adding butylphthalide, stirring at 65 to 90°C for more than 90 to 150 minutes, cooling to obtain an inclusion compound solution; taking another 10% of water that does not exceed the prescribed amount, adding a flavoring agent, adding it to the inclusion compound solution after all of it is dissolved, adding water to the full volume, stirring to mix, adjusting the solution pH to the target value, filtering, filling, and sterilizing.

[0057] Preferably, the preparation method of the above-mentioned oral solution comprises the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75°C to 90°C, stirring and adding the prescribed amount of cyclodextrin or its derivatives to completely dissolve, adding pharmaceutically acceptable excipients, stirring to completely dissolve, adding butylphthalide, stirring at 65 to 90°C for more than 90 to 150 minutes, and cooling to obtain an inclusion compound solution; taking another 10% of water not exceeding the prescribed amount, adding a flavoring agent, adding it to the inclusion compound solution after all the water is dissolved, adding water to the full volume, stirring and mixing, adjusting the pH of the solution to the target value, filtering, filling, and sterilizing.

[0058] Furthermore, in the above-mentioned oral solution, the therapeutically effective amount is a single daily dose, which, after administration to human subjects, for each 1 mg of butylphthalide, achieves an average Cmax of from 1.2 ng / ml to 3.2 ng / ml; preferably an average Cmax of from 1.7 ng / ml to 3.2 ng / ml; more preferably an average Cmax of from 2.2 ng / ml to 2.6 ng / ml.

[0059] Furthermore, in the above-mentioned oral solution, the therapeutically effective amount is a single daily dose, which, after administration to human subjects, for each 1 mg of butylphthalide, achieves an average Cmax of from 1.2 ng / ml to 3.2 ng / ml; preferably an average Cmax of from 1.5 ng / ml to 2.6 ng / ml; more preferably an average Cmax of from 2.2 ng / ml to 2.6 ng / ml.

[0060] Further, in the above oral solution, the therapeutically effective amount is a single daily dose of 120 mg, and wherein the single daily dose achieves an average Cmax within the range of 80% to 125% of 175 ng / ml.

[0061] Further, in the above oral solution, the therapeutically effective amount is a single daily dose of 125 mg, and wherein the single daily dose achieves an average Cmax within the range of 80% to 125% of 272 ng / ml.

[0062] Further, in the above oral solution, the therapeutically effective amount is a single daily dose of 136 mg, and wherein the single daily dose achieves an average Cmax within the range of 80% to 125% of 304 ng / ml.

[0063] Further, in the above oral solution, the therapeutically effective amount is a single daily dose of 160 mg, and wherein the single daily dose achieves an average Cmax within the range of 80% to 125% of 410 ng / ml.

[0064] Further, in the above oral solution, the therapeutically effective amount is a single daily dose of 120 mg, and wherein the single daily dose achieves an average AUC (0-24h) or average AUC (0-t) in the range of 80% to 125% of 308h*ng / ml.

[0065] Further, in the above oral solution, the therapeutically effective amount is a single daily dose of 125 mg, and wherein the single daily dose achieves an average AUC (0-24h) or average AUC (0-t) in the range of 80% to 125% of 310h*ng / ml.

[0066] Further, in the above oral solution, the therapeutically effective amount is a single daily dose of 136 mg, and wherein the single daily dose achieves an average AUC (0-24h) or average AUC (0-t) in the range of 80% to 125% of 332h*ng / ml.

[0067] Further, in the above oral solution, the therapeutically effective amount is a single daily dose of 160 mg, and wherein the single daily dose achieves an average AUC (0-24h) or average AUC (0-t) in the range of 80% to 125% of 478h*ng / ml.

[0068] Further, in the above oral solution, the therapeutically effective amount is a single daily dose of 120 mg, and wherein the single daily dose achieves an average AUC (0-inf) within the range of 80% to 125% of 338 h*ng / ml.

[0069] Further, in the above oral solution, the therapeutically effective amount is a single daily dose of 125 mg, and wherein the single daily dose achieves an average AUC (0-inf) within the range of 80% to 125% of 340 h*ng / ml.

[0070] Further, in the above oral solution, the therapeutically effective amount is a single daily dose of 136 mg, and wherein the single daily dose achieves an average AUC (0-inf) within the range of 80% to 125% of 367 h*ng / ml.

[0071] Further, in the above oral solution, the therapeutically effective amount is a single daily dose of 160 mg, and wherein the single daily dose achieves an average AUC (0-inf) within the range of 80% to 125% of 514 h*ng / ml.

[0072] Furthermore, in the above-mentioned oral solution, the disease includes cerebral ischemic disease, Alzheimer's disease or kidney disease; preferably, the cerebral ischemic disease includes ischemic stroke; preferably, it is mild, moderate or severe acute ischemic stroke.

[0073] In addition, the present invention also provides a preparation method of the above-mentioned oral solution, comprising the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75° C. to 90° C., adding the prescribed amount of cyclodextrin or its derivatives and pharmaceutically acceptable excipients at one time or in batches under stirring, stirring to completely dissolve, adding butylphthalide, stirring at 65 to 90° C. for more than 90 to 150 minutes, cooling to obtain an inclusion complex solution, adding water to make up the full volume, stirring and mixing, adjusting the solution pH to the target value, filtering, filling, and sterilizing.

[0074] Preferably, the above method comprises the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75°C to 90°C, adding the prescribed amount of cyclodextrin or its derivatives with stirring to completely dissolve, adding pharmaceutically acceptable excipients, stirring to completely dissolve, adding butylphthalide, stirring at 65 to 90°C for more than 90 to 150 minutes, cooling to room temperature to obtain an inclusion complex solution, adding water to make up the full volume, stirring and mixing, adjusting the pH of the solution to the target value, filtering, filling, and sterilizing.

[0075] Furthermore, the above method includes the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75°C to 90°C, adding the prescribed amount of cyclodextrin or its derivatives and pharmaceutically acceptable excipients at one time or in batches while stirring, stirring to completely dissolve, adding butylphthalide, stirring at 65 to 90°C for more than 90 to 150 minutes, and cooling to obtain an inclusion compound solution; taking another 10% of water that does not exceed the prescribed amount, adding a flavoring agent, adding it to the inclusion compound solution after all of it is dissolved, adding water to the full volume, stirring to mix, adjusting the pH of the solution to the target value, filtering, filling, and sterilizing.

[0076] Preferably, the above method comprises the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75°C to 90°C, adding the prescribed amount of cyclodextrin or its derivatives with stirring to completely dissolve, adding pharmaceutically acceptable excipients, stirring to completely dissolve, adding butylphthalide, stirring at 65 to 90°C for more than 90 to 150 minutes, and cooling to obtain an inclusion compound solution; taking another 10% of water not exceeding the prescribed amount, adding a flavoring agent, adding it to the inclusion compound solution after all the water is dissolved, adding water to the full volume, stirring to mix, adjusting the pH of the solution to the target value, filtering, filling, and sterilizing.

[0077] Furthermore, the cooling in the above-mentioned "cooling to obtain the inclusion compound solution" is preferably reduced to room temperature.

[0078] Special Notes: The "butylphthalide" mentioned in the present invention includes but is not limited to racemic butylphthalide and levorotatory butylphthalide. The mass of butylphthalide in the specific prescription is C 12 H 14 O2 calculation.

[0079] The water mentioned in the present invention includes but is not limited to purified water, ultrapure water, and distilled water.

[0080] The room temperature of the present invention refers to: 20°C ~ 35°C, preferably 25°C ~ 30°C.

[0081] The "inf" in the AUC (0-inf) described in the present invention is the abbreviation of the English word "infinite".

[0082] The container of the butylphthalide oral solution of the present invention includes but is not limited to a soda-lime glass tube oral liquid bottle, a low borosilicate glass tube oral liquid bottle, a medium borosilicate glass tube oral liquid bottle, an oral liquid medicinal polyester bottle, an oral liquid medicinal polypropylene bottle, an oral liquid medicinal high-density polyethylene bottle, etc. The container of the butylphthalide oral solution is colorless or brown.

[0083] The “above” or “below” mentioned in the present invention include the number itself; “not exceeding” or “not exceeding” do not include the number itself.

[0084] Hydroxypropyl-β-cyclodextrin is a pocket-like structure, with hydrophilicity on the outside and lipophilicity on the inside; therefore, wrapping water-insoluble substances in its pocket structure to form a drug-cyclodextrin inclusion complex can enhance the water solubility of the insoluble substances. However, studies have shown that in order to achieve complete dissolution of butylphthalide (clear solution state), the molar amount of hydroxypropyl-β-cyclodextrin needs to be more than twice the molar amount of butylphthalide, which means that the butylphthalide-hydroxypropyl-β-cyclodextrin inclusion complex is not an ideal 1:1 molecular state, but an aggregate form of two or more cyclodextrin or drug-cyclodextrin inclusion molecules or other forms of inclusion complexes. In some cases, these inclusion complexes can produce opalescence, but in most cases the particle size of the inclusion complex is still much smaller than the wavelength of visible light, so it only exists as a clear solution. For the clear solution state, it is generally considered to be a homogeneous fluid, so drug registration generally does not conduct particle size research on clear liquid preparations, and the prior art has not seen any particle size research on butylphthalide liquid preparations. However, for the oral solution of butylphthalide, the applicant unexpectedly found that the particle size of the inclusion complex in the butylphthalide oral solution is a key factor affecting the bioavailability stability of the butylphthalide oral solution. When the inclusion complex particle size does not exceed 10 nm, the in vivo Cmax, Tmax, and AUC parameter levels of different 0-day samples are similar. However, when the particle size and its intensity peak area (Peak One Area by Intensity) are controlled at the same time, the bioavailability stability of the butylphthalide oral solution at different particle sizes shows huge differences.

[0085] Beneficial Effects : On the one hand, the butylphthalide oral solution of the present invention adopts an inclusion compound particle size of 1nm~8nm, which can stably improve bioavailability, and has a faster onset of action, stable quality, and reliable efficacy. Compared with the reference preparation (butylphthalide soft capsule, Enbipu®), the 125mg butylphthalide oral solution of the present invention can reach the AUC level equivalent to the reference preparation, but the Cmax is much higher than the reference preparation, and the Tmax is smaller, the onset of action is faster, the bioavailability is higher, and the therapeutic effect is guaranteed. In particular, after the butylphthalide oral solution of the present invention has been subjected to a three-year stability study, when the inclusion compound particle size and its intensity peak area are controlled to be not less than 90%, the various bioavailability parameters of the butylphthalide oral solution remain stable, the efficacy is stable and reliable, and it is more suitable for the special treatment needs of diseases in this field. On the other hand, the present application first discovered that by adding inorganic salts and acidifiers during the process of cyclodextrin inclusion of butylphthalide to form butylphthalide-cyclodextrin inclusion complex, it is beneficial to control the size of the inclusion complex particles and the particle size stability, so that the preparation process of the butylphthalide oral solution of the present invention does not need to consider the complex equipment or process requirements for preparing the particle size, and is more suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1This is a particle size detection diagram of the 0-day butylphthalide oral solution of Example 2. DETAILED DESCRIPTION

[0087] The scheme of the present invention will be explained below in conjunction with examples. It will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. The specific techniques or conditions not indicated in the examples are carried out according to the techniques or conditions described in the literature in this area or according to the product specifications. The reagents or instruments used that do not indicate the manufacturer are all conventional products obtained through commercial purchase.

[0088] Example 1: Butylphthalide solution and its preparation

[0089]

[0090] Take 60%~70% of the prescribed amount of purified water and heat it to 80℃~90℃, add the prescribed amount of hydroxypropyl-β-cyclodextrin, sodium chloride, and 0.01M hydrochloric acid solution with stirring, stir to completely dissolve, add butylphthalide, stir at 70℃~80℃ for more than 120 minutes, cool to room temperature to obtain inclusion complex solution, add purified water to make up to the full volume, stir and mix, adjust the solution pH to the target value with 0.01M hydrochloric acid solution or 0.01M sodium hydroxide solution, filter with 0.45μm filter membrane, divide and fill into 100 bottles, and sterilize at 121℃ for 15 minutes.

[0091] 0.01M hydrochloric acid or 0.01M hydrochloric acid solution refers to 0.01mol / L hydrochloric acid aqueous solution. 0.01M sodium hydroxide solution refers to 0.01mol / L sodium hydroxide aqueous solution. The following examples and comparative examples are explained in the same way.

[0092] Example 2: Butylphthalide solution and its preparation

[0093]

[0094] Take 60%~70% of the prescribed amount of purified water and heat it to 80℃~90℃, stir and add the prescribed amount of hydroxypropyl-β-cyclodextrin, sodium chloride, citric acid and sodium citrate, stir to completely dissolve, add butylphthalide, stir at 70℃~80℃ for more than 120 minutes, cool to room temperature to obtain inclusion complex solution, add purified water to make up to the full volume, stir and mix, adjust the solution pH to the target value with an appropriate amount of 10% citric acid solution or 10% sodium citrate solution, filter with 0.45μm filter membrane, divide and fill into 100 tubes, and sterilize at 121℃ for 15 minutes.

[0095] 10% citric acid solution means that the mass of citric acid contained in 100 ml of water is 10 g. 10% sodium citrate solution means that the mass of sodium citrate contained in 100 ml of water is 10 g. The following examples and comparative examples are explained in the same way.

[0096] Example 3: Butylphthalide solution and its preparation

[0097]

[0098] Take 70%~80% of the prescribed amount of purified water and heat it to 75℃~85℃, stir and add the prescribed amount of hydroxypropyl-β-cyclodextrin to completely dissolve it, add sodium chloride, citric acid and sodium citrate, stir to completely dissolve it, add butylphthalide, stir at 70℃~80℃ for more than 120 minutes, cool to room temperature to obtain inclusion complex solution, add purified water to make up to the full volume, stir and mix, adjust the solution pH to the target value with an appropriate amount of 10% citric acid solution or 10% sodium citrate solution, filter with 0.45μm filter membrane, divide and fill into 100 tubes, and sterilize at 121℃ for 15 minutes.

[0099] Example 4: Butylphthalide solution and its preparation

[0100]

[0101] The preparation method is the same as Example 2.

[0102] Example 5: Butylphthalide solution and its preparation

[0103]

[0104] Take 50%~60% of the prescribed amount of purified water and heat it to 80℃~90℃, stir and add the prescribed amount of hydroxypropyl-β-cyclodextrin to completely dissolve it, add sodium chloride, citric acid and sodium citrate, stir to completely dissolve it, add butylphthalide, stir at 80℃~90℃ for more than 90 minutes, cool to room temperature to obtain inclusion complex solution, add purified water to make up to the full volume, stir and mix, adjust the solution pH to the target value with an appropriate amount of 10% citric acid solution or 10% sodium citrate solution, filter with 0.45μm filter membrane, divide and fill into 100 tubes, and sterilize at 121℃ for 15 minutes.

[0105] Example 6: Butylphthalide solution and its preparation

[0106]

[0107] Take 70%~80% of the prescribed amount of purified water and heat it to 80℃~90℃, stir and add the prescribed amount of hydroxypropyl-β-cyclodextrin to completely dissolve it, add sodium chloride, citric acid and sodium citrate, stir to completely dissolve it, add butylphthalide, stir at 65℃~80℃ for more than 90 minutes, cool to room temperature to obtain inclusion complex solution, add purified water to make up to the full volume, stir and mix, adjust the solution pH to the target value with an appropriate amount of 10% citric acid solution or 10% sodium citrate solution, filter with 0.45μm filter membrane, divide and fill into 100 tubes, and sterilize at 121℃ for 15 minutes.

[0108] Example 7: Butylphthalide solution and its preparation

[0109]

[0110] The preparation method is the same as Example 6.

[0111] Example 8: Butylphthalide solution and its preparation

[0112]

[0113] Take 50%~60% of the prescribed amount of purified water and heat it to 80℃~90℃, stir and add the prescribed amount of hydroxypropyl-β-cyclodextrin to completely dissolve it, add sodium chloride, citric acid and sodium citrate, stir to completely dissolve it, add butylphthalide, stir at 80℃~90℃ for more than 90 minutes, and cool to room temperature to obtain an inclusion compound solution; take another 5% of the prescribed amount of purified water, add the prescribed amount of flavoring agent (sucralose, sweet orange flavor), stir to dissolve and then add to the aforementioned inclusion compound solution, stir and mix, add purified water to the full volume, stir and mix, adjust the solution pH to the target value with an appropriate amount of 10% citric acid solution or 10% sodium citrate solution, filter with a 0.45μm filter membrane, fill in 100 tubes, and sterilize at 121℃ for 15 minutes.

[0114] Example 9: Butylphthalide solution and its preparation

[0115]

[0116] The preparation method is the same as Example 3.

[0117] Example 10: Butylphthalide solution and its preparation

[0118]

[0119] The preparation method is the same as Example 3.

[0120] Example 11: Butylphthalide oral solution and its preparation

[0121] The preparation method is the same as Example 3.

[0122] Comparative Example 1: Butylphthalide solution and its preparation

[0123]

[0124] Weigh the prescribed amount of hydroxypropyl-β-cyclodextrin and sodium chloride, add to 80% of the total volume, 80°C purified water, and stir to completely dissolve. Weigh the prescribed amount of butylphthalide, add to the hydroxypropyl-β-cyclodextrin solution, stir for 120 minutes, and completely dissolve. Cool to room temperature, add 0.01M hydrochloric acid solution to adjust the pH to the target value, add purified water to the total volume, stir and mix, filter with a 0.45μm filter membrane, and fill in 100 equal parts, and sterilize at 121°C for 15 minutes.

[0125] Comparative Example 2: Butylphthalide solution and its preparation

[0126]

[0127] Weigh the prescription amount of hydroxypropyl-β-cyclodextrin, pour in 50% of the prescription amount of purified water, stir and heat to 80°C, and keep warm for 14 minutes. Take another prescription amount of butylphthalide, pour it into the hydroxypropyl-β-cyclodextrin solution, stir magnetically for 120 minutes, and observe a clear and transparent inclusion solution without butylphthalide oil droplets. Add purified water to the inclusion solution to 80% of the prescription amount, add the prescription amount of sodium chloride, use 0.05M hydrochloric acid and 0.05M sodium hydroxide to adjust the solution pH to the target value, add purified water to the full amount, stir and mix, filter with a 0.45μm filter membrane, and fill it into 100 bottles in equal parts, and sterilize at 121°C for 15 minutes.

[0128] 0.05M hydrochloric acid and 0.05M sodium hydroxide both refer to molar mass concentrations, which are: 0.05mol / L hydrochloric acid aqueous solution and 0.05mol / L sodium hydroxide aqueous solution, respectively.

[0129] Comparative Example 3: Butylphthalide solution and its preparation

[0130]

[0131] Weigh the prescribed amount of hydroxypropyl-β-cyclodextrin, citric acid, and sodium citrate, add purified water at a temperature of 80-90°C that accounts for 65% of the total volume, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 80-90°C for 80-90 min until completely dissolved, then cool to room temperature, make up to the full volume with purified water, adjust the pH value of the solution to the target value with 10% citric acid or 10% sodium citrate; filter through a 0.45μm filter membrane, divide and fill into 100 bottles, and sterilize at 121°C for 15 minutes.

[0132] Comparative Example 4: Butylphthalide solution and its preparation

[0133]

[0134] Weigh the prescribed amount of hydroxypropyl-β-cyclodextrin, citric acid, and sodium citrate, add 50-60% 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 80-90min until completely dissolved, then cool to room temperature to obtain an inclusion complex solution; weigh the prescribed amount of sodium chloride, sucralose, and sweet orange flavor, add the prescribed amount of 5% purified water, stir to dissolve, add to the aforementioned inclusion complex solution, stir and mix, then make up to the full volume with purified water, adjust the pH value of the solution to the target value with 10% citric acid or 10% sodium citrate; filter with a 0.45μm filter membrane, divide and fill into 100 tubes, and sterilize at 121°C for 15 minutes.

[0135] Comparative Example 5: Butylphthalide solution and its preparation

[0136]

[0137] Weigh the prescribed amount of hydroxypropyl-β-cyclodextrin, sodium chloride and sodium citrate, add purified water at a temperature of 75-80°C accounting for 60% of the total volume, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 75-80°C for 90 minutes, and cool the solution to room temperature after it is completely dissolved; make up to the full volume with purified water, adjust the pH of the solution to the target value with 10% citric acid or 10% sodium citrate; filter through a 0.45μm filter membrane, and equally fill into 100 bottles; sterilize at 121°C for 15 minutes.

[0138] Test Example 1: Stability Study The samples of Examples 1 to 11 and Comparative Examples 1 to 5 were subjected to a long-term stability study for three years (25°C ± 2°C, RH 60% ± 5%), and samples were taken and tested at 0 days, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, and 36 months, respectively, to observe the properties of the solution, the pH value of the test solution, the content of butylphthalide, the maximum single impurity, the total impurity, the visible foreign matter and the particle size and its intensity peak area (Peak One Area by Intensity (%)).

[0139] (1) Detection method for relevant substances and contents: adopt the corresponding detection method of Test Example 2 of patent CN202210631226.6.

[0140] (2) Visible foreign matter: Determined according to the first method (light inspection method) of General Chapter 0904 of the Chinese Pharmacopoeia 2020 Edition. If the number of foreign matter visible to the naked eye is 0, it is A; if the number is 1 to 5, it is B, both of which meet the standard; if the number is more than 6, it is C.

[0141] (3) Particle size: Malvern Zetasiser Pro, test temperature 25°C, dispersion medium water, direct test of this product (no dilution required).

[0142] According to the sampling test results of each sample at 0 days, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months and 36 months, each index of each sample gradually changes in the same direction, that is, there is no sudden increase and decrease or sudden decrease and increase in any index of each sample. Therefore, in order to highlight the difference, only the representative test point data are displayed, that is, the stability data of each sample at 0 days, 12 months and 36 months. The statistical results are shown in Tables 1 and 2 below:

[0143]

[0144] The above stability statistical results show that the properties, pH value, maximum single impurity, total impurity, content and visible foreign matter stability of Examples 1 to 11 and Comparative Examples 1 to 5 are basically the same, but there is a huge difference in particle size. The study found that in the process of hydroxypropyl-β-cyclodextrin inclusion of butylphthalide to form butylphthalide-hydroxypropyl-β-cyclodextrin inclusion complex, inorganic salts and acidity agents are crucial to improving the stability of the inclusion complex. The inventors of the present application surprisingly found that when inorganic salts and acidity agents (Examples 1 to 11) were added, the particle size stability of the inclusion complex was better, mainly manifested in that the intensity peak area (Peak One Area by Intensity (%)) of the particle size could be maintained at more than 90%, or even more than 95%, proving that inorganic salts and acidity agents are beneficial to improving the stability of the particle size of the inclusion complex; and when the inclusion complex was formed, whether only inorganic salts were added (Comparative Example 1, Comparative Example 5), or only acidity agents were added (Comparative Example 3, Comparative Example 4), or inorganic salts and acidity agents were added after the inclusion complex was formed (Comparative Example 2), the particle size of the inclusion complex showed a certain degree of instability, specifically manifested in that the intensity peak area of ​​the particle size was less than 90%, and with the long-term stability investigation, the intensity peak area was greatly reduced.

[0145] Experimental Example 2: Pharmacokinetic study in animals 1. Purpose: To investigate the pharmacokinetic characteristics of the test preparation of butylphthalide oral solution and the reference preparation of butylphthalide soft capsule (ENBIP®) in Naïve Beagle dogs after oral gavage. On the one hand, to compare the absorption rate and extent of butylphthalide in plasma after taking the two preparations and evaluate the bioequivalence of the two preparations. On the other hand, to compare the pharmacodynamic stability of each test preparation.

[0146] 2. Test preparations: 22 test preparations in total, including butylphthalide oral solutions of Examples 1 to 8 and Comparative Examples 3 to 5 that had undergone stability tests for 0 days and 36 months in Test Example 1.

[0147] 3. Test method: For each test preparation, 8 Naïve Beagle dogs (half male and half female) were used and divided into two groups, marked as Group 1 and Group 2, with half male and half female in each group. Cycle I: Group 1 animals were given 1 vial (136 mg / vial) of butylphthalide oral solution (test preparation) by oral gavage after fasting, and Group 2 animals were given 2 capsules (100 mg / capsule) of butylphthalide soft capsules (Enbipu®, reference preparation) by oral gavage after fasting. The animals were washed off for 7 days before administration in Cycle II. Cycle II: Group 1 animals were given 2 capsules (100 mg / capsule) of butylphthalide soft capsules (reference preparation) by oral gavage after fasting, and Group 2 animals were given 1 vial (136 mg / capsule) of butylphthalide oral solution (test preparation) by oral gavage after fasting. Blood samples were collected 24 hours after administration. The concentration of butylphthalide in plasma samples was quantified by LC-MS / MS analysis. The main pharmacokinetic parameters were calculated by non-compartmental model using Phoenix WinNonlin®8.3 software based on the blood drug concentration data, and the bioavailability of the test preparation compared with the reference preparation was evaluated.

[0148] 4. Test results:

[0149] The above table shows that the 0-day and 36-month samples of Examples 1 to 8 and Comparative Examples 3 to 4 are superior to the reference preparation of butylphthalide soft capsules (Enbipu®) in terms of bioavailability parameters such as Cmax, Tmax, AUC (0-24h), and AUC (0-inf). Specifically, all 136mg butylphthalide oral solution test preparations have a Tmax shortened by about 70% and a faster onset of action compared to the 200mg butylphthalide soft capsule reference preparation, and Cmax increased by about 70%, AUC (0-24h) increased by nearly 30%, and AUC (0-inf) increased by about 10%, proving that the 136mg low-dose butylphthalide oral solution has better bioavailability and better effect. Secondly, after 36 months of stability study, the bioavailability stability of the samples of the examples is better than that of the comparative samples. For example, the 36-month butylphthalide oral solution samples of Examples 1-8 have a relative bioavailability (GMR%) variation of no more than 2 unit points compared to their 0-day samples, and Tmax remains basically unchanged; while the 36-month samples of Comparative Examples 3 to 5 have a variation of nearly 5 unit points compared to their 0-day samples, proving that the particle size, especially the intensity peak area of ​​the particle size, is not conducive to the stable release of the sample when it is lower than 90%. The applicant speculates that the possible reason is that when the intensity peak area is too low, it means that the inclusion complex has partially excessively aggregated, which in turn leads to slower release to varying degrees. In addition, combined with the stability investigation data of Test Example 1, it can be expected that the samples of Examples 9 to 11 have similar bioavailability stability as those of Examples 1 to 8 above after 36 months of long-term stability investigation, and it is expected to improve bioavailability.

[0150] Experimental Example 3: Pharmacokinetic Study in Human Body 1. Purpose of the study: To investigate the pharmacokinetic characteristics of the test preparation butylphthalide oral solution and the reference preparation butylphthalide soft capsule (ENBIP®) in healthy subjects after a single oral administration in the fasting state. On the one hand, to compare the absorption rate and extent of butylphthalide in plasma after taking the two preparations and evaluate the bioequivalence of the two preparations. On the other hand, to compare the pharmacodynamic stability of each test preparation.

[0151] 2. Test preparations: 10 test preparations in total, including butylphthalide oral solutions of Example 2, Example 9, Example 10, Example 11 and Comparative Example 5, which were subjected to stability tests for 0 days and 36 months in Test Example 1.

[0152] 3. Experimental methods: A single-center, single oral, fasting administration, randomized, open, parallel control design was adopted. 132 healthy subjects were included, half of them were male and half were female, and they were randomly divided into 11 groups, with 12 people in each group. Under fasting conditions, they randomly took a single oral dose of butylphthalide oral solution (test preparation), 1 bottle each time (wherein Example 2 and Comparative Example 5 are both 136 mg / piece, Example 9 is 125 mg / piece, Example 10 is 160 mg / piece, and Example 11 is 120 mg / piece); or under fasting conditions, a single oral dose of butylphthalide soft capsules (Enbipu®, reference preparation) was taken, 200 mg each time (100 mg / capsule). Blood samples were collected until 72 hours after administration. The concentration of butylphthalide in plasma samples was quantified by LC-MS / MS analysis. Based on the blood drug concentration data, the main pharmacokinetic parameters were calculated using Phoenix WinNonlin®8.3 software using a non-compartmental model.

[0153] 4. Test results:

[0154] The above table shows that the human bioavailability of the butylphthalide oral solution of Examples 2, 9, 10, 11 and Comparative Example 5 is better than that of the reference preparation (butylphthalide soft capsule, Enbipu®), which is specifically manifested in that the Tmax of the butylphthalide oral solution of each example and comparative example is about 65% faster than that of the reference preparation, and the onset of action is faster, while the Cmax is higher than that of the reference preparation, and the AUC (0-24h) and AUC (0-inf) are not less than 80% of the reference preparation, which ensures sufficient efficacy, proving that the butylphthalide oral solution of the present invention only needs 120 mg at least to achieve the same therapeutic effect as 200 mg butylphthalide soft capsule. In addition, the data in the above table show that the stability of the bioavailability of the butylphthalide oral solution of the embodiment is better than that of the comparative example. After a long-term three-year stability test, the bioavailability of Examples 2, 9, 10, and 11 remains basically unchanged, while the bioavailability of Comparative Example 5 decreases by nearly 10%, proving that the butylphthalide oral solution of the present invention has a stable therapeutic effect. Accordingly, according to the difference in stability between the embodiment and the comparative example, it can be further proved that the particle size of the butylphthalide oral solution is the key to affecting the bioavailability, and controlling the particle size and its intensity peak area can improve the bioavailability stability of the butylphthalide oral solution.

[0155] The above description is only a preferred embodiment of the present invention. It should be pointed out that professionals in this technical field can implement various modifications to these embodiments without departing from the technical principles of the present invention, and these modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Use of butylphthalide in preparing an oral solution for treating and / or preventing ischemic stroke, characterized in that: The oral solution comprises a therapeutically effective amount of butylphthalide and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount is a single daily dose, and after administration to human subjects, for each 1 mg of butylphthalide, the single daily dose reaches an average Cmax from 1.2 ng / ml to 3.2 ng / ml, and the single daily dose is 120 mg to 160 mg.

2. The use according to claim 1, characterized in that The butylphthalide is an inclusion compound of cyclodextrin or its derivatives, and the particle size of the inclusion compound is 1nm~8nm, preferably 3nm~6nm.

3. The use according to claim 2, characterized in that The intensity peak area of ​​the inclusion compound particle size is not less than 90%, preferably not less than 95%.

4. The use according to any one of claims 1 to 3, characterized in that: The cyclodextrin or its derivative is hydroxypropyl-β-cyclodextrin, and the mass ratio of butylphthalide to hydroxypropyl-β-cyclodextrin is 1:19-25.

5. The use according to any one of claims 1 to 3, characterized in that: The pharmaceutically acceptable excipient is an inclusion excipient, and the inclusion excipient comprises an inorganic salt and an acidifier.

6. The use according to claim 5, characterized in that The inorganic salt comprises sodium chloride, potassium chloride, lithium chloride, magnesium chloride, ammonium chloride, aluminum chloride, ferrous chloride, ferric chloride, sodium sulfate, magnesium sulfate, ammonium sulfate, sodium carbonate or sodium polyphosphate; the acidifier comprises hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, glacial acetic acid or a buffer pair; the buffer pair comprises citric acid and citrate, citric acid and phosphate, lactic acid and lactate, phosphoric acid and phosphate, acetic acid and acetate, or tartaric acid and tartrate.

7. The use according to claim 5, characterized in that The mass ratio of the inorganic salt to butylphthalide is 0.05-1.0:1; the mass ratio of the acidity agent to butylphthalide is 0.01-0.15:

1.

8. The use according to any one of claims 1 to 3, characterized in that: The pH value of the oral solution is 3.5-5.

5.

9. The use according to any one of claims 1 to 3, characterized in that: The oral solution also includes a flavoring agent; the flavoring agent includes one or more of a sweetener, a flavoring agent, a sour agent, and a salty agent.

10. The use according to claim 9, characterized in that The preparation method of the oral solution comprises the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75° C. to 90° C., adding the prescribed amount of cyclodextrin or its derivatives and pharmaceutically acceptable excipients at one time or in batches under stirring, stirring to completely dissolve, adding butylphthalide, stirring at 65° C. to 90° C. for more than 90 to 150 minutes, cooling to obtain an inclusion compound solution; taking another 10% of water not exceeding the prescribed amount, adding a flavoring agent, adding the flavoring agent to the inclusion compound solution after all the water is dissolved, adding the water to the full volume, stirring to mix, adjusting the pH of the solution to the target value, filtering, filling, and sterilizing.

11. The use according to any one of claims 1 to 8, characterized in that: The preparation method of the oral solution comprises the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75° C. to 90° C., adding the prescribed amount of cyclodextrin or its derivatives and pharmaceutically acceptable excipients at one time or in batches under stirring, stirring to completely dissolve, adding butylphthalide, stirring at 65° C. to 90° C. for more than 90 to 150 minutes, cooling to obtain an inclusion complex solution, adding water to make up the full volume, stirring and mixing, adjusting the solution pH to the target value, filtering, filling, and sterilizing.

12. The use according to any one of claims 1 to 11, characterized in that: The therapeutically effective amount is a single 120 mg daily dose, and wherein the single daily dose achieves a mean Cmax within the range of 80% to 125% of 175 ng / ml.

13. The use according to any one of claims 1 to 11, characterized in that: The therapeutically effective amount is a single 125 mg daily dose, and wherein the single daily dose achieves a mean Cmax within the range of 80% to 125% of 272 ng / ml.

14. The use according to any one of claims 1 to 11, characterized in that: The therapeutically effective amount is a single 136 mg daily dose, and wherein the single daily dose achieves a mean Cmax within the range of 80% to 125% of 304 ng / ml.

15. The use according to any one of claims 1 to 11, characterized in that: The therapeutically effective amount is a single 160 mg daily dose, and wherein the single daily dose achieves a mean Cmax within the range of 80% to 125% of 410 ng / ml.

16. The use according to any one of claims 1 to 11, characterized in that: The therapeutically effective amount is a single 125 mg daily dose, and wherein the single daily dose achieves a mean AUC(0-24h) or mean AUC(0-t) in the range of 80% to 125% of 310 h*ng / ml.

17. The use according to any one of claims 1 to 11, characterized in that: The therapeutically effective amount is a single 136 mg daily dose, and wherein the single daily dose achieves a mean AUC(0-24h) or mean AUC(0-t) within the range of 80% to 125% of 332h*ng / ml.

18. The use according to any one of claims 1 to 11, characterized in that: The therapeutically effective amount is a single 160 mg daily dose, and wherein the single daily dose achieves a mean AUC(0-24h) or mean AUC(0-t) within the range of 80% to 125% of 478h*ng / ml.

19. The use according to any one of claims 1 to 11, characterized in that: The therapeutically effective amount is a single 125 mg daily dose, and wherein the single daily dose achieves a mean AUC(0-inf) within the range of 80% to 125% of 340 h*ng / ml.

20. The use according to any one of claims 1 to 11, characterized in that: The therapeutically effective amount is a single 136 mg daily dose, and wherein the single daily dose achieves a mean AUC(0-inf) within the range of 80% to 125% of 367 h*ng / ml.

21. The use according to any one of claims 1 to 11, characterized in that: The therapeutically effective amount is a single 160 mg daily dose, and wherein the single daily dose achieves a mean AUC(0-inf) within the range of 80% to 125% of 514 h*ng / ml.

22. The use according to any one of claims 1 to 11, characterized in that: The therapeutically effective amount is a single 120 mg daily dose, and wherein the single daily dose achieves an average AUC(0-24h) or an average AUC(0-t) within the range of 80% to 125% of 308h*ng / ml, or an average AUC(0-inf) within the range of 80% to 125% of 338h*ng / ml.

23. An oral solution of butylphthalide for treating and / or preventing diseases, the oral solution comprising a therapeutically effective amount of butylphthalide and a pharmaceutically acceptable excipient, characterized in that: The butylphthalide is an inclusion compound of cyclodextrin or its derivatives, the particle size of the inclusion compound is 1nm~8nm, and the specification of butylphthalide is 120mg~160mg.

24. The oral solution according to claim 23, characterized in that The intensity peak area of ​​the inclusion compound particle size is not less than 90%, preferably not less than 95%.

25. The oral solution according to claim 23, characterized in that The particle size of the inclusion compound is 3nm~6nm.

26. The oral solution according to any one of claims 23 to 24, characterized in that The cyclodextrin or its derivative is hydroxypropyl-β-cyclodextrin, and the mass ratio of butylphthalide to hydroxypropyl-β-cyclodextrin is 1:19-25.

27. The oral solution according to any one of claims 23 to 24, characterized in that The pharmaceutically acceptable excipient is an inclusion excipient, and the inclusion excipient includes an inorganic salt and an acidifier.

28. The oral solution according to claim 27, characterized in that The inorganic salt comprises sodium chloride, potassium chloride, lithium chloride, magnesium chloride, ammonium chloride, aluminum chloride, ferrous chloride, ferric chloride, sodium sulfate, magnesium sulfate, ammonium sulfate, sodium carbonate or sodium polyphosphate; the acidifier comprises hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, glacial acetic acid or a buffer pair; the buffer pair comprises citric acid and citrate, citric acid and phosphate, lactic acid and lactate, phosphoric acid and phosphate, acetic acid and acetate, or tartaric acid and tartrate.

29. The oral solution according to claim 27, characterized in that The mass ratio of the inorganic salt to butylphthalide is 0.05-1.0:1; the mass ratio of the acidity agent to butylphthalide is 0.01-0.15:

1.

30. The oral solution according to any one of claims 23 to 29, characterized in that: The pH value of the oral solution is 3.5-5.

5.

31. The oral solution according to any one of claims 23 to 29, characterized in that: The oral solution also includes a flavoring agent; the flavoring agent includes one or more of a sweetener, a flavoring agent, a sour agent, and a salty agent.

32. The oral solution according to any one of claims 23 to 31, characterized in that The therapeutically effective amount is a single daily dose that achieves a mean Cmax of from 1.2 ng / ml to 3.2 ng / ml per 1 mg of butylphthalide after administration to human subjects.

33. The oral solution according to any one of claims 23 to 32, characterized in that: The therapeutically effective amount is a single 120 mg daily dose, and wherein the single daily dose achieves a mean Cmax within the range of 80% to 125% of 175 ng / ml.

34. The oral solution according to any one of claims 23 to 32, characterized in that The therapeutically effective amount is a single 125 mg daily dose, and wherein the single daily dose achieves a mean Cmax within the range of 80% to 125% of 272 ng / ml.

35. The oral solution according to any one of claims 23 to 32, characterized in that: The therapeutically effective amount is a single 136 mg daily dose, and wherein the single daily dose achieves a mean Cmax within the range of 80% to 125% of 304 ng / ml.

36. The oral solution according to any one of claims 23 to 32, characterized in that: The therapeutically effective amount is a single 160 mg daily dose, and wherein the single daily dose achieves a mean Cmax within the range of 80% to 125% of 410 ng / ml.

37. The oral solution according to any one of claims 23 to 32, characterized in that The therapeutically effective amount is a single 125 mg daily dose, and wherein the single daily dose achieves a mean AUC(0-24h) or mean AUC(0-t) in the range of 80% to 125% of 310 h*ng / ml.

38. The oral solution according to any one of claims 23 to 32, characterized in that: The therapeutically effective amount is a single 136 mg daily dose, and wherein the single daily dose achieves a mean AUC(0-24h) or mean AUC(0-t) within the range of 80% to 125% of 332h*ng / ml.

39. The oral solution according to any one of claims 23 to 32, characterized in that: The therapeutically effective amount is a single 160 mg daily dose, and wherein the single daily dose achieves a mean AUC(0-24h) or mean AUC(0-t) within the range of 80% to 125% of 478h*ng / ml.

40. The oral solution according to any one of claims 23 to 32, characterized in that: The therapeutically effective amount is a single 125 mg daily dose, and wherein the single daily dose achieves a mean AUC(0-inf) within the range of 80% to 125% of 340 h*ng / ml.

41. The oral solution according to any one of claims 23 to 32, characterized in that The therapeutically effective amount is a single 136 mg daily dose, and wherein the single daily dose achieves a mean AUC(0-inf) within the range of 80% to 125% of 367 h*ng / ml.

42. The oral solution according to any one of claims 23 to 32, characterized in that The therapeutically effective amount is a single 160 mg daily dose, and wherein the single daily dose achieves a mean AUC(0-inf) within the range of 80% to 125% of 514 h*ng / ml.

43. The oral solution according to any one of claims 23 to 32, characterized in that The therapeutically effective amount is a single 120 mg daily dose, and wherein the single daily dose achieves an average AUC(0-24h) or an average AUC(0-t) within the range of 80% to 125% of 308h*ng / ml, or an average AUC(0-inf) within the range of 80% to 125% of 338h*ng / ml.

44. The oral solution according to any one of claims 23 to 43, characterized in that The disease includes cerebral ischemic disease, Alzheimer's disease or kidney disease; preferably, the cerebral ischemic disease includes ischemic stroke, preferably mild, moderate or severe acute ischemic stroke.

45. A method for preparing the oral solution according to any one of claims 23 to 30, 32 to 44, characterized in that: The method comprises the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75°C to 90°C, adding the prescribed amount of cyclodextrin or its derivatives and pharmaceutically acceptable excipients at one time or in batches under stirring, stirring to completely dissolve, adding butylphthalide, stirring at 65°C to 90°C for more than 90 to 150 minutes, cooling to obtain an inclusion complex solution, adding water to make the volume full, stirring and mixing, adjusting the pH of the solution to a target value, filtering, filling, and sterilizing.

46. ​​A method for preparing the oral solution according to any one of claims 31, 32 to 44, characterized in that: The method comprises the following steps: taking 50% to 80% of the prescribed amount of water and heating it to 75°C to 90°C, adding the prescribed amount of cyclodextrin or its derivatives and pharmaceutically acceptable excipients at one time or in batches under stirring, stirring to completely dissolve, adding butylphthalide, stirring at 65°C to 90°C for more than 90 to 150 minutes, cooling to obtain an inclusion compound solution; taking another 10% of water not exceeding the prescribed amount, adding a flavoring agent, adding the flavoring agent to the inclusion compound solution after all the water is dissolved, adding water to the full volume, stirring to mix, adjusting the pH of the solution to the target value, filtering, filling, and sterilizing.

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