Pharmaceutical active composition containing butylphthalide and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition containing butylphthalide and a preparation method thereof, the pharmaceutical composition is composed of butylphthalide and a derivative of butylphthalide, and the derivative of butylphthalide comprises hydroxyl butylphthalide and optionally comprises one or more of butylene phthalide and propylphthalide. The pharmaceutical composition can be used for treating mild and moderate acute ischemic cerebral apoplexy, is stable in quality, remarkably improves side effects such as anorexia caused by abdominal discomfort, and can improve the clinical curative effect and medication safety of a butylphthalide preparation.

Description

[0001] This application is a divisional application of the invention patent application with application number CN202211332097.7 and invention name “A pharmaceutically active composition containing butylphthalide and its preparation method” submitted by the applicant on October 28, 2022. Technical Field

[0002] The invention relates to the technical field of medicines, and in particular to a pharmaceutically active composition containing butylphthalide and butylphthalide derivatives and a preparation method thereof. Background Art

[0003] The chemical name of butylphthalide is 3-butyl-l(H)-isobenzofuranone, which is racemic-3-n-butylphthalide, also known as apigenin. It was first extracted from celery seeds. It is a colorless or light yellow clear oily liquid with a specific aroma. It is easily degraded under light and high temperature conditions. The structure of butylphthalide is as follows: .

[0004] Since butylphthalide was first approved for marketing in 2005, its marketed products are still retained in CSPC Pharmaceutical Group's Enbipu, namely butylphthalide soft capsules and butylphthalide sodium chloride injection, which are used to treat mild and moderate acute ischemic stroke. In the Phase II and III clinical studies of butylphthalide, the main adverse reactions were mild to excessive elevation of aminotransferase, occasional nausea, abdominal discomfort and mental symptoms. The applicant has conducted a quality comparison study on Enbipu and found that there are many impurity peaks in the chromatogram of its related substances; and according to the patent information disclosure content of the China Listed Drug Patent Information Registration Platform, both butylphthalide soft capsules and butylphthalide sodium chloride injection have disclosed the invention name of "A butylphthalide pharmaceutically active composition and its preparation method" patent ZL 201210184391.8, and at the same time claim the drug combination containing active ingredients of claims 1 to 12 of the patent; and according to the records of the patent, its butylphthalide pharmaceutically active composition contains more than a dozen alkenylphthalides and alkylphthalides, mainly including butylphthalide derivatives such as butylenephthalide, pentylphthalide, phthalide and propylphthalide, and the content of a single butylphthalide derivative is far more than 0.1%; specifically, the content of any component of its alkenylphthalide impurities can reach up to 0.5%, and the content of any component of its alkylphthalide impurities can reach up to 1.0%. In addition, many existing technologies and forced degradation tests of butylphthalide show that the main degradation impurity of butylphthalide is hydroxybutylphthalide, and the raw materials and preparations of the existing technology do not control this impurity. Therefore, it is of clinical significance to optimize the composition of the pharmaceutical active composition of butylphthalide and control the content of butylphthalide derivatives to reduce adverse reactions and improve its drug safety. Summary of the invention

[0005] In view of this, in order to solve at least one of the above technical problems, the present invention provides a pharmaceutically active composition containing butylphthalide and its derivatives and a preparation method thereof. The pharmaceutically active composition provided by the present invention has few adverse reactions, stable properties, and meets clinical needs.

[0006] The invention provides a pharmaceutically active composition, which comprises butylphthalide and a derivative of butylphthalide, wherein the derivative of butylphthalide comprises hydroxybutylphthalide.

[0007] Furthermore, the above-mentioned derivative of butylphthalide also contains any one or both of alkenylphthalide and alkylphthalide.

[0008] Furthermore, the alkenylphthalide is selected from any one or more of methylenephthalide, vinylphthalide, propylenephthalide, butylenephthalide, and pentylphthalide; and the alkylphthalide is selected from any one or more of phthalide, toluenephthalide, ethylphthalide, propylphthalide, and pentylphthalide.

[0009] The derivative structure of the above-mentioned butylphthalide is as follows: .

[0010] Furthermore, the content of butylphthalide in the above-mentioned pharmaceutically active composition is ≥98.0%, the content of butylphthalide derivatives is >0 and ≤2.0%, wherein the content of hydroxybutylphthalide is not more than 1.0%, and the content of any other butylphthalide derivatives is not more than 0.1%; preferably, the content of butylphthalide in the above-mentioned pharmaceutically active composition is ≥99.0%, the content of butylphthalide derivatives is >0 and ≤1.0%, wherein the content of hydroxybutylphthalide is not more than 0.5%, and the content of any other butylphthalide derivatives is not more than 0.1%.

[0011] Furthermore, the content of butylphthalide in the above-mentioned pharmaceutically active composition is ≥98.5%, the content of butylphthalide derivatives is >0 and ≤1.5%, wherein the content of hydroxybutylphthalide is no more than 1.0%, and any content of other butylphthalide derivatives is no more than 0.1%; preferably, the content of butylphthalide in the above-mentioned pharmaceutically active composition is ≥99.5%, the content of butylphthalide derivatives is >0 and ≤0.5%, wherein the content of hydroxybutylphthalide is no more than 0.2%, and any content of other butylphthalide derivatives is no more than 0.1%; more preferably, the content of butylphthalide in the above-mentioned pharmaceutically active composition is ≥99.5%, the content of butylphthalide derivatives is >0 and ≤0.5%, wherein the content of hydroxybutylphthalide is no more than 0.2%, and any content of other butylphthalide derivatives is no more than 0.05%.

[0012] Furthermore, the above-mentioned derivative of butylphthalide is selected from any one or more of hydroxybutylphthalide, butylenephthalide and propylphthalide.

[0013] Preferably, the derivatives of butylphthalide are selected from hydroxybutylphthalide. Optionally, the derivatives of butylphthalide also include any one or two of butylenephthalide and propylphthalide.

[0014] The present invention provides a method for preparing any of the above-mentioned pharmaceutically active compositions, comprising the following steps: A. Lactone ring opening: Add the crude butylphthalide to an alcohol solvent at room temperature, add a strong base under stirring, reflux and stir until the reaction is complete, cool to room temperature, add methyl tert-butyl ether, keep stirring at 5±5℃ for 2-5h to precipitate solids, filter and wash to obtain a filter cake, and dry to obtain a lactone ring-opening product carboxylate; B. Pickling: Add the lactone ring-opening product carboxylate into water at room temperature and stir to dissolve, add weak acid to adjust the pH of the solution to acidic, precipitate solid, and filter to obtain the lactone ring-opening product; C. Lactone ring closure: Add the lactone ring-opening product into water at room temperature and stir to dissolve, add concentrated hydrochloric acid, heat to 40℃±10℃ and stir to react for 3-5h, add methyl tert-butyl ether at room temperature for extraction, wash the organic phase with alkaline solution and water, dry and concentrate to obtain an oily substance, i.e., semi-crude butylphthalide; D. Purification of butylphthalide: The semi-crude butylphthalide is subjected to reduced pressure distillation by an oil pump, and the fractions at 150-200° C. are collected to obtain a butylphthalide pharmaceutically active composition.

[0015] Furthermore, the preparation method of any of the above-mentioned pharmaceutically active compositions comprises the following steps: A. Lactone ring opening: add the crude butylphthalide to 2-10 times the mass ratio of alcohol solvent at room temperature, add 1.0-2.0 molar equivalent of strong base under stirring, reflux and stir until the reaction is complete, cool to room temperature, add 6-15 times the mass ratio of methyl tert-butyl ether, keep warm and stir at 5±5℃ for 2-5h to precipitate solid, filter and wash to obtain filter cake, and dry to obtain lactone ring opening product carboxylate; B. Pickling: Add the lactone ring-opening product carboxylate to water at a mass ratio of 6 to 15 times at room temperature, stir and dissolve, add weak acid to adjust the pH of the solution to acidic, precipitate solids, and filter to obtain the lactone ring-opening product; C. Lactone ring closure: add the lactone ring-opening product to water in a 2-8 times mass ratio at room temperature, stir and dissolve, add 0.1-2.0 molar equivalent of concentrated hydrochloric acid, heat to 40°C±10°C, stir and react for 3-5 hours, add methyl tert-butyl ether at room temperature for extraction, wash the organic phase with alkaline solution and water, dry and concentrate to obtain an oily substance, i.e., semi-crude butylphthalide; D. Purification of butylphthalide: The semi-crude butylphthalide is subjected to reduced pressure distillation by an oil pump, and the fractions at 150-200° C. are collected to obtain a butylphthalide pharmaceutically active composition.

[0016] Furthermore, the amount of the weak acid used in the pickling reaction of step B is 1.2 to 5.0 molar equivalents relative to the built-in ring-opening product carboxylate.

[0017] Furthermore, in the above preparation method: in the ring-opening reaction of step A, the feeding ratios of alcohol solvent, strong base, and methyl tert-butyl ether relative to the crude butylphthalide are 2 to 10 times by mass ratio, 1.0 to 2.0 molar equivalents, and 6 to 15 times by mass ratio, respectively; in the pickling reaction of step B, the feeding ratios of water and weak acid relative to the lactone ring-opening product carboxylate are 6 to 15 times by mass ratio and 1.2 to 5.0 molar equivalents, respectively; in the ring-closing reaction of step C, the feeding ratios of water and concentrated hydrochloric acid relative to the lactone ring-opening product are 2 to 8 times by mass ratio and 0.1 to 2.0 molar equivalents, respectively.

[0018] Furthermore, in any of the above preparation methods, the alcohol solvent in step A includes methanol, ethanol, propanol, isopropanol or tert-butanol, the strong base includes sodium hydroxide and potassium hydroxide; the weak acid in step B includes citric acid, tartaric acid or acetic acid; the alkaline solution in step C includes saturated sodium bicarbonate aqueous solution, 1-10% sodium hydroxide aqueous solution or 1-10% potassium hydroxide aqueous solution. Wherein, the percentage "%" is the mass percentage.

[0019] Furthermore, in step D of any of the above preparation methods, it is preferred to collect a fraction at 150-180°C.

[0020] It is particularly noted that the mass ratio or molar equivalent of the synthesis process of the present invention is the ratio of the material in each step to the starting material in the corresponding step.

[0021] The present invention provides a pharmaceutical preparation, which comprises any of the above-mentioned pharmaceutically active compositions and a pharmaceutically acceptable carrier. Optionally, the pharmaceutical composition further contains other therapeutic components.

[0022] Furthermore, the above-mentioned pharmaceutical preparation is an oral preparation, preferably an oral solution, tablet, soft capsule, sustained-release tablet or pill.

[0023] Furthermore, the above-mentioned pharmaceutical preparation is an injection preparation, preferably an injection solution, a small water injection, a lyophilized powder injection or an intravenous emulsion.

[0024] The present invention also provides the use of any of the above-mentioned butylphthalide pharmaceutical active compositions, or any of the above-mentioned butylphthalide pharmaceutical compositions, in the preparation of drugs for treating mild or moderate acute ischemic stroke.

[0025] Beneficial EffectsOn the one hand, the active pharmaceutical composition of butylphthalide described in the present invention optimizes the composition of butylphthalide derivatives, and all indicators meet the requirements of pharmaceutical use. The quality is stable during the storage process, and the gastrointestinal side effects such as abdominal discomfort caused by the prior art butylphthalide can be improved, so that the product has fewer adverse reactions, stable properties, and meets more clinical needs. On the other hand, the preparation method of the active pharmaceutical composition of butylphthalide provided by the present invention adopts the process of "lactone ring opening-acid washing-lactone ring closing-distillation refining", with fewer side reactions, controllable impurities, short production cycle, energy saving and environmental protection, and suitable for large-scale production. DETAILED DESCRIPTION

[0026] Below will be explained the scheme of the present invention in conjunction with test examples and embodiments.It will be appreciated by those skilled in the art that each example below is only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.The specific technology or conditions not indicated in each example are carried out according to the technology or conditions described in the document in this area or according to the product specification.The reagents or instruments used that do not indicate the manufacturer are conventional products obtained by commercial purchase.

[0027] Detection method of butylphthalide and its derivatives: Determination by high performance liquid chromatography Chromatographic conditions and system suitability test: 5-fluorophenylpropyl bonded silica gel was used as filler; 10 mmol / L potassium dihydrogen phosphate solution (pH adjusted to 3.0 with phosphoric acid) was used as mobile phase A, isopropanol: methanol: acetonitrile (5:45:100) was used as mobile phase B, and gradient elution was performed; the detection wavelength was 230 nm; the injection volume was 10 μl, the flow rate was 1.0 ml / min, and the column temperature was 35 °C.

[0028] The gradient elution program is as follows: .

[0029] Test solution: Take an appropriate amount of butylphthalide sample, accurately weigh it, dissolve it in acetonitrile and quantitatively dilute it to make a solution containing about 1.0 mg of butylphthalide per 1 ml as the test solution. Take 20 μl of the test solution and inject it into the liquid chromatograph. Record the chromatogram until all peaks have appeared, and calculate the content of each component by the area normalization method.

[0030] Comparative Example 1: A butylphthalide pharmaceutically active composition was prepared according to Example 6 of patent CN102716121B.

[0031] Comparative Example 2: High-purity butylphthalide was prepared according to Example 1 of patent CN111961018B.

[0032] Comparative Example 3: Butylphthalide Pharmaceutically Active Composition (1) Lactone ring-opening: add 1 kg of crude butylphthalide to 5 kg (5 times by mass) of methanol at room temperature, add 0.59 kg of potassium hydroxide (2.0 molar equivalent) while stirring, reflux and stir until the reaction is complete, cool to room temperature, add 10 kg (10 times by mass) of methyl tert-butyl ether, keep stirring at 5±5°C for 3 h to precipitate solid, filter with suction, wash with methyl tert-butyl ether to obtain a filter cake, and dry the filter cake at 55±5°C to constant weight to obtain the lactone ring-opening product carboxylate.

[0033] (2) Lactone ring closure: Add 1 kg of lactone ring-opening product carboxylate salt into 10 kg (10 times by mass) of water at room temperature and stir to dissolve. Add concentrated hydrochloric acid to adjust the pH value of the solution to 2.5. Heat to 40°C ± 5°C and stir to react for 3-4 hours. No solid is observed in the reaction system. Add methyl tert-butyl ether and extract twice at room temperature. Combine the organic phases and wash once with 1% aqueous sodium hydroxide solution and finally wash once with water. Dry with anhydrous sodium sulfate and concentrate to dryness to obtain an oily substance, i.e., semi-crude butylphthalide.

[0034] (3) Purification of butylphthalide: The semi-crude butylphthalide is distilled under reduced pressure by an oil pump, and the fraction at 150-200°C is collected to obtain a butylphthalide pharmaceutically active composition.

[0035] Example 1: Butylphthalide Pharmaceutically Active Composition A. Lactone ring-opening: add 1 kg of crude butylphthalide to 8 kg (8 times by mass) of isopropanol at room temperature, add 0.41 kg of potassium hydroxide (1.4 molar equivalent) under stirring, reflux and stir until the reaction is complete, cool to room temperature, add 10 kg (10 times by mass) of methyl tert-butyl ether, keep warm and stir at 5±5°C for 3 hours to precipitate solid, filter with suction, wash with methyl tert-butyl ether to obtain a filter cake, and dry the filter cake at 55±5°C to constant weight to obtain a lactone ring-opening product carboxylate.

[0036] B. Acid washing: add 1 kg of lactone ring-opening product carboxylate salt to 10 L (10 times mass ratio) of water at room temperature, stir and dissolve, adjust the solution pH to acidic with 1.72 kg of citric acid (2.2 molar equivalents), precipitate solid, and filter to obtain lactone ring-opening product.

[0037] C. Lactone ring closure: Add 0.81 kg of lactone ring-opening product into 2.43 kg (3 times mass ratio) of water at room temperature, stir and dissolve, add 0.38 kg (1.0 molar equivalent) of concentrated hydrochloric acid, raise the temperature to 40℃±5℃, stir and react for 3-4 hours, no solid is observed in the reaction system; add methyl tert-butyl ether and extract twice at room temperature, combine the organic phases, wash once with 1% sodium hydroxide aqueous solution, and finally wash once with water, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain an oily substance, i.e., semi-crude butylphthalide.

[0038] D. Purification of butylphthalide: The semi-crude butylphthalide is subjected to reduced pressure distillation by an oil pump, and the fractions at 150-180° C. are collected to obtain a butylphthalide pharmaceutically active composition.

[0039] Example 2: Butylphthalide Pharmaceutically Active Composition A. Lactone ring-opening: add 1 kg of crude butylphthalide to 2 kg (2 times by mass) of methanol at room temperature, add 0.58 kg of potassium hydroxide (2.0 molar equivalent) under stirring, reflux and stir until the reaction is complete, cool to room temperature, add 15 kg (15 times by mass) of methyl tert-butyl ether, keep warm and stir at 5±5°C for 5 hours to precipitate solid, filter with suction, wash with methyl tert-butyl ether to obtain filter cake, and dry the filter cake at 55±5°C to constant weight to obtain lactone ring-opening product carboxylate.

[0040] B. Acid washing: add 1 kg of lactone ring-opening product carboxylate salt to 6 L (6 times mass ratio) of water at room temperature, stir and dissolve, adjust the solution pH to acidic with 0.29 kg of acetic acid (about 1.2 molar equivalents), precipitate solid, and filter to obtain lactone ring-opening product.

[0041] C. Lactone ring closure: Add 0.77 kg of lactone ring-opening product into 2 kg (2 times mass ratio) of water at room temperature, stir and dissolve, add 0.038 kg (0.1 molar equivalent) of concentrated hydrochloric acid, raise the temperature to 45°C±5°C, stir and react for 3-4 hours, and no solid is observed in the reaction system; add methyl tert-butyl ether and extract twice at room temperature, combine the organic phases, wash once with saturated sodium bicarbonate aqueous solution, and finally wash once with water, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain an oily substance, i.e., semi-crude butylphthalide.

[0042] D. Purification of butylphthalide: The crude butylphthalide is subjected to reduced pressure distillation by an oil pump, and the fractions at 150-200° C. are collected to obtain a butylphthalide pharmaceutically active composition.

[0043] Example 3: Butylphthalide Pharmaceutically Active Composition A. Lactone ring-opening: add 1 kg of crude butylphthalide to 10 kg (10 times by mass) of isopropanol at room temperature, add 0.29 kg of potassium hydroxide (1.0 molar equivalent) under stirring, reflux and stir until the reaction is complete, cool to room temperature, add 6 kg (6 times by mass) of methyl tert-butyl ether, keep warm and stir at 5±5°C for 3 hours to precipitate solid, filter with suction, wash with methyl tert-butyl ether to obtain a filter cake, and dry the filter cake at 55±5°C to constant weight to obtain a lactone ring-opening product carboxylate.

[0044] B. Acid washing: add 1 kg of lactone ring-opening product carboxylate salt to 15 L (15 times mass ratio) of water at room temperature and stir to dissolve, adjust the pH of the solution to acidic with 2.35 kg (about 3.0 molar equivalents) of citric acid, precipitate solid, and filter to obtain the lactone ring-opening product.

[0045] C. Lactone ring closure: Add 0.83 kg of lactone ring-opening product into 8 kg (8 times mass ratio) of water at room temperature, stir and dissolve, add 0.76 kg (2.0 molar equivalent) of concentrated hydrochloric acid, raise the temperature to 35°C±5°C, stir and react for 3-4 hours, and no solid is observed in the reaction system; add methyl tert-butyl ether and extract twice at room temperature, combine the organic phases, wash once with 1% sodium hydroxide aqueous solution, and finally wash once with water, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain an oily substance, i.e., semi-crude butylphthalide.

[0046] D. Purification of butylphthalide: The semi-crude butylphthalide is subjected to reduced pressure distillation by an oil pump, and the fractions at 150-180° C. are collected to obtain a butylphthalide pharmaceutically active composition.

[0047] Example 4: Butylphthalide Pharmaceutically Active Composition A. Lactone ring-opening: add 1 kg of crude butylphthalide to 5 kg (5 times by mass) of ethanol at room temperature, add 0.41 kg of sodium hydroxide (1.4 molar equivalent) under stirring, reflux and stir until the reaction is complete, cool to room temperature, add 10 kg (10 times by mass) of methyl tert-butyl ether, keep warm and stir at 5±5°C for 2 hours to precipitate solid, filter with suction, wash with methyl tert-butyl ether to obtain a filter cake, and dry the filter cake at 55±5°C to constant weight to obtain a lactone ring-opening product carboxylate.

[0048] B. Acid washing: add 1 kg of lactone ring-opening product carboxylate salt to 10 kg (10 times mass ratio) of water at room temperature and stir to dissolve, adjust the solution pH to acidic with 1.21 kg of acetic acid (5.0 molar equivalent), precipitate solid, and filter to obtain lactone ring-opening product.

[0049] C. Lactone ring closure: Add 0.86 kg of lactone ring-opening product into 5 kg (5 times mass ratio) of water at room temperature, stir and dissolve, add 0.41 kg of concentrated hydrochloric acid (1.0 molar equivalent), raise the temperature to 40℃±5℃, stir and react for 4-5 hours, and no solid is observed in the reaction system; add methyl tert-butyl ether and extract twice at room temperature, combine the organic phases, wash once with 10% sodium hydroxide aqueous solution, and finally wash once with water, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain an oily substance, i.e., semi-crude butylphthalide.

[0050] D. Purification of butylphthalide: The semi-crude butylphthalide is subjected to reduced pressure distillation by an oil pump, and the fractions at 160-180° C. are collected to obtain a butylphthalide pharmaceutically active composition.

[0051] Test Example 1: Quality Study of Butylphthalide Pharmaceutically Active Composition

[0052] According to the requirements of the relevant guidelines for stability tests, the butylphthalide samples of Examples 1 to 4 and Comparative Example 3 were subjected to accelerated stability tests (40°C ± 2°C; RH: 75% ± 5%). The results are shown in Table 1.

[0053] .

[0054] Notes: (1) The above-mentioned butylphthalide derivatives refer to hydroxybutylphthalide, alkenylphthalide (including cis and trans isomers, such as methylenephthalide, vinylphthalide, propylenephthalide, butylenephthalide, pentylphthalide) and alkylphthalide (such as phthalide, toluenephthalide, ethylphthalide, propylphthalide, pentylphthalide). The butylphthalide derivatives not listed in the above table are not detected in the samples; (2) The above-mentioned other largest single impurities are other known and unknown impurities except butylphthalide derivatives.

[0055] The results of the 6-month accelerated stability test of the butylphthalide samples in the above table show that the total impurities of the samples of Examples 1 to 4 of the present invention increased by about 0.1%, and the butylphthalide content decreased by about 0.1%, proving that the quality of the butylphthalide pharmaceutically active composition of the present invention is stable; while the total impurities of Comparative Example 3 increased by more than 0.7%, and the butylphthalide content decreased by more than 0.7%, proving that the butylphthalide pharmaceutically active composition of Comparative Example 3 is relatively unstable. Based on this, it can be inferred that when the butylphthalide content in the pharmaceutically active composition of butylphthalide is not less than 98.0%, the content of total butylphthalide derivatives is not more than 2.0%, the content of hydroxybutylphthalide is not more than 1.0%, and the content of any other butylphthalide derivative is not more than 0.1%, the sample is accelerated and stable; especially when the butylphthalide content in the pharmaceutically active composition of butylphthalide is not less than 99.5%, the content of total butylphthalide derivatives is not more than 0.5%, the content of hydroxybutylphthalide is not more than 0.2%, and the content of any other butylphthalide derivative is not more than 0.1%, the sample is accelerated and stable.

[0056] Combined with the prior art, the characteristics and advantages of the synthesis process of the present invention are summarized as follows: (1) The process of the present invention can effectively remove various impurities, especially the impurities of butylphthalide derivatives. (2) The post-opening treatment of the present invention adopts weak acid pickling, and only needs to control the solution to reach an acidic environment, without the need to strictly control the pH value to a precise range; in addition, compared with the salt recrystallization process of the prior art, the pickling operation step has fewer process links, simpler operation, and saves materials and production time. (3) Pickling can reduce the amount of concentrated hydrochloric acid used in the subsequent ring-closing reaction, greatly reduce the risk of impurity generation, and can prevent the risk of equipment corrosion to a greater extent. (4) The stirring solid temperature of the ring-opening step and the reaction temperature of the ring-closing step of the present invention are both room temperature. Compared with the high temperature or low temperature reaction conditions of the prior art, the equipment requirements are low and the energy consumption is lower; in addition, the ring-closing reaction of the present invention can be completely reacted in 3 to 5 hours, which is much lower than the more than ten hours of the prior art, greatly shortening the production cycle. In summary, the preparation process of the butylphthalide pharmaceutical active composition of the present invention is suitable for large-scale production, has a short production cycle, is energy-saving, green and environmentally friendly, has few impurities, and has stable and controllable product quality.

[0057] Example 5: Butylphthalide oral solution API: the butylphthalide pharmaceutically active composition prepared in Example 1; Prescription composition: , Preparation method: Weigh the prescribed amount of hydroxypropyl-β-cyclodextrin 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 25-30°C after it is completely dissolved; make up to volume with purified water, adjust the pH of the solution to 4.0 with 10% (w / v) citric acid; filter with a 0.8μm filter membrane, and fill in 100 equal portions; sterilize at 121°C for 15 minutes.

[0058] Example 6: Butylphthalide oral solution API: the butylphthalide pharmaceutically active composition prepared in Example 3; The formulation composition and preparation are the same as in Example 5.

[0059] Example 7: Butylphthalide oral solution API: the butylphthalide pharmaceutically active composition prepared in Example 4; The formulation composition and preparation are the same as in Example 5.

[0060] Example 8: Butylphthalide Sodium Chloride Injection API: the butylphthalide pharmaceutically active composition prepared in Example 1; Prescription composition: , Preparation method: Take the prescribed amount of purified water, boil it and cool it to 80°C. Weigh 80g of sodium sulfobutyl beta-cyclodextrin (substitution degree 6.2-6.9, average substitution degree 6.4, molecular weight 2145.2g / mol) and 90g of sodium chloride, add them to 8L of purified water at 80°C, and stir to dissolve completely. Weigh 2.5g of butylphthalide, add it to the sodium sulfobutyl beta-cyclodextrin solution, stir it in an oil bath at 80°C for 90min to dissolve completely. Cool to room temperature, add 0.2M hydrochloric acid solution to adjust the pH to 4.5, and add purified water to 10L. Filter it through a 0.45μm filter membrane using a circulating water multi-purpose vacuum pump. Fill the prepared solution at 100ml / tube. After filling, sterilize it at high temperature at 121°C for 15 minutes to obtain the sample of the embodiment.

[0061] Example 9: Butylphthalide small water injection API: the butylphthalide pharmaceutically active composition prepared in Example 3; Prescription composition: , Preparation method: Weigh the prescribed amount of butylphthalide and HS-15, stir at 60-70℃ for 90-120 minutes to completely dissolve the butylphthalide; cool to 25-30℃, add purified water, stir and mix, and then adjust the volume to the total capacity; adjust the pH value of the solution to 4.0 with 1mol / L hydrochloric acid solution; filter with 0.45μm filter membrane, fill according to 180 equal parts (10ml / tube), and sterilize at 121℃ for 15 minutes; nitrogen protection is used throughout the process.

[0062] Example 10: Butylphthalide intravenous emulsion API: the butylphthalide pharmaceutically active composition prepared in Example 3; The prescription composition and preparation method are the same as Example 14 of patent CN102716121A.

[0063] Embodiment 11: Butylphthalide soft capsule API: the butylphthalide pharmaceutically active composition prepared in Example 1; The prescription composition and preparation method are the same as Example 10 of patent CN102716121A.

[0064] Comparative Example 4: Commercially available butylphthalide soft capsules (batch number: 1182201102).

[0065] Comparative Example 5: Commercially available butylphthalide sodium chloride injection (batch number: 6182007106).

[0066] Comparative Example 6: Butylphthalide Oral Solution API: the active pharmaceutical composition of butylphthalide prepared in Comparative Example 3; The formulation composition and preparation are the same as in Example 5.

[0067] Experiment 2: Stability study of butylphthalide pharmaceutical composition According to the relevant guidelines for stability testing, the butylphthalide preparations of Examples 5 to 11 and Comparative Examples 4 to 6 were subjected to accelerated stability testing (40°C ± 2°C; RH: 75% ± 5%). The results are shown in Tables 2 and 3.

[0068]

[0069]

[0070] As can be seen from the above table: in the 6-month accelerated test, the number and content of related substances of the butylphthalide preparations of Examples 5 to 11 are stable, and the content of butylphthalide is also stable, proving that the pharmaceutical composition of the present invention is stable, and the stability of the pharmaceutical preparation is consistent with the stability of the butylphthalide pharmaceutically active composition, and further proving that the excipient compatibility of the butylphthalide pharmaceutically active composition of the present invention is strong. In the 6-month accelerated test, the total impurities of Comparative Examples 4 and 5 increased significantly, and the number of impurities was significantly more than that of the present invention embodiment preparation, especially the total impurity content of the commercially available soft capsule of Comparative Example 4 exceeded 1.0%, the total impurities increased, and the number of impurities was close to 20, which was much higher than that of the present invention embodiment preparation. Therefore, the comparison results of Examples 5 to 11 with Comparative Examples 4 to 5 prove that the butylphthalide pharmaceutical composition of the present invention has better quality and is more stable. In addition, Examples 5 to 11 and Comparative Example 6 show that the butylphthalide pharmaceutically active composition is stable, and the obtained butylphthalide pharmaceutical preparation is stable, that is, the stability of the butylphthalide pharmaceutically active composition affects the stability of the pharmaceutical preparation. Accordingly, by controlling the butylphthalide content in the butylphthalide pharmaceutically active composition to be not less than 98.0%, the content of butylphthalide derivatives to be not more than 2.0%, wherein the content of hydroxybutylphthalide is not more than 1.0%, and the content of any other butylphthalide derivatives is not more than 0.1%, a stable butylphthalide active pharmaceutical composition and a stable butylphthalide pharmaceutical preparation can be obtained.

[0071] Test Example 3: Single-dose acute toxicity test in mice and rats 1. Test samples: Comparative Example 1, Comparative Example 3, Example 2, Example 3, Example 4.

[0072] 2. Sample processing: Place the above materials in a clean dosing container, add appropriate amount of Solutol to dissolve, vortex and shake, add pure water, ultrasonicate, and vortex and shake until the compound is completely dissolved (prepare and use immediately).

[0073] 3. Experimental methods: (1) Single-dose toxicity test in rats: Several healthy adult SD rats weighing 150-160g, half male and half female, were randomly divided into several groups, with 10 rats in each group. Single-dose toxicity tests were conducted on Comparative Example 1, Comparative Example 3, Example 2, Example 3, and Example 4 in the present invention using the "median lethal dose method". All animals were fasted 12 hours before administration and had free access to water. On the day of administration, each group was gavaged with the corresponding drug, with a gavage volume of 5 ml / kg. The toxic reactions and deaths of the rats within 7 days after the single administration were observed, and the LD 50 value.

[0074] (2) Single-dose toxicity test in mice: Several healthy adult ICR mice weighing 18-22g, half male and half female, were randomly divided into several groups, with 10 mice in each group. Single-dose toxicity tests were conducted on Comparative Example 1, Comparative Example 3, Example 2, Example 3, and Example 4 in the present invention using the "median lethal dose method". All animals were fasted for 12 hours before administration and had free access to water. On the day of administration, each group was gavaged with the corresponding drug, with a gavage volume of 0.1ml / 10g. The toxic reactions and deaths of mice within 7 days after a single dose were observed, and the LD 50 value.

[0075] 4. Experimental results:

[0076] It can be seen from the above results that the LD50 values ​​of the pharmaceutically active butylphthalide compositions of Examples 2 to 4 of the present invention are significantly higher than those of Comparative Examples 1 and 3 in both rats and mice, indicating that the toxicity of the pharmaceutically active butylphthalide compositions of the examples after single administration is lower than that of Comparative Examples 1 and 3, and the pharmaceutically active butylphthalide composition of Example 3 is particularly safe.

[0077] Test Example 4: Effects of continuous drug administration on general state and food intake in rats 1. Experimental purpose: To investigate the effects of each compound in the examples on the food intake of rats after continuous oral administration for 14 days, and to indirectly evaluate the effects of each compound on the gastrointestinal tract of rats.

[0078] 2. Test substances and their preparation: (1) Test samples: Example 1, Example 2, Example 3, Example 4, Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4.

[0079] (2) Sample processing: Place the above materials in a clean dosing container, add an appropriate amount of Solutol to dissolve, vortex and shake, add pure water, sonicate, and vortex and shake until the compound is completely dissolved (prepare and use immediately).

[0080] 3. Trial groups and drug administration:

[0081] 4. Test methods: SD rats were randomly divided into two groups, 10 in each group. The corresponding drugs or solvents were given by gavage once a day. After 14 consecutive days, the effects of the drugs on the food intake of the rats were observed and recorded.

[0082] 5. Test results: .

[0083] As can be seen from the above table, compared with the blank group, the food intake of the rats in Example 1 to 4 groups within 24 hours after the last administration was basically the same as that of the blank group, with no statistical difference; while the food intake of the rats in the comparative example 1 to 4 groups within 24 hours after the last administration was extremely significantly reduced compared with the blank group, and there was a statistical difference (P<0.01); it proves that the pharmaceutically active composition of butylphthalide of the present invention can significantly reduce side effects such as gastrointestinal discomfort.

[0084] The above descriptions are only preferred embodiments 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. A method for preparing a butylphthalide pharmaceutically active composition, characterized in that: The preparation method comprises the following steps: A. Lactone ring opening: Add the crude butylphthalide to an alcohol solvent at room temperature, add a strong base under stirring, reflux and stir until the reaction is complete, cool to room temperature, add methyl tert-butyl ether, keep stirring at 5±5℃ for 2-5h to precipitate solids, filter and wash to obtain a filter cake, and dry to obtain a lactone ring-opening product carboxylate; B. Pickling: Add the lactone ring-opening product carboxylate into water at room temperature and stir to dissolve, add weak acid to adjust the pH of the solution to acidic, precipitate solid, and filter to obtain the lactone ring-opening product; C. Lactone ring closure: Add the lactone ring-opening product into water at room temperature and stir to dissolve, add concentrated hydrochloric acid, heat to 40℃±10℃ and stir to react for 3-5h, add methyl tert-butyl ether at room temperature for extraction, wash the organic phase with alkaline solution and water, dry and concentrate to obtain an oily substance, i.e., semi-crude butylphthalide; D. Purification of butylphthalide: The semi-crude butylphthalide is subjected to reduced pressure distillation by an oil pump, and the fractions at 150 to 200° C. are collected to obtain a butylphthalide pharmaceutically active composition.

2. The preparation method according to claim 1, characterized in that: The alcohol solvent in step A includes methanol, ethanol, propanol, isopropanol or tert-butanol, and the strong base includes sodium hydroxide and potassium hydroxide; the weak acid in step B includes citric acid, tartaric acid or acetic acid; the alkaline solution in step C includes saturated sodium bicarbonate aqueous solution, 1-10% sodium hydroxide aqueous solution or 1-10% potassium hydroxide aqueous solution.

3. A pharmaceutically active composition of butylphthalide, characterized in that: The pharmaceutically active composition comprises butylphthalide and a derivative of butylphthalide, wherein: the content of butylphthalide in the pharmaceutically active composition is ≥98.0%, and the content of the butylphthalide derivative is >0 and ≤2.0%; wherein the butylphthalide derivative comprises: (1) hydroxybutylphthalide; (2) optionally, one or both of alkenylphthalide and alkylphthalide; The pharmaceutically active composition is obtained by the following method: A. Lactone ring opening: Add the crude butylphthalide to an alcohol solvent at room temperature, add a strong base under stirring, reflux and stir until the reaction is complete, cool to room temperature, add methyl tert-butyl ether, keep stirring at 5±5℃ for 2-5h to precipitate solids, filter and wash to obtain a filter cake, and dry to obtain a lactone ring-opening product carboxylate; B. Pickling: Add the lactone ring-opening product carboxylate into water at room temperature and stir to dissolve, add weak acid to adjust the pH of the solution to acidic, precipitate solid, and filter to obtain the lactone ring-opening product; C. Lactone ring closure: Add the lactone ring-opening product into water at room temperature and stir to dissolve, add concentrated hydrochloric acid, heat to 40℃±10℃ and stir to react for 3-5h, add methyl tert-butyl ether at room temperature for extraction, wash the organic phase with alkaline solution and water, dry and concentrate to obtain an oily substance, i.e., semi-crude butylphthalide; D. Purification of butylphthalide: The semi-crude butylphthalide is subjected to reduced pressure distillation by an oil pump, and the fractions at 150 to 200° C. are collected to obtain a butylphthalide pharmaceutically active composition.

4. The pharmaceutically active composition according to claim 3, characterized in that The content of butylphthalide is ≥98.5%, preferably ≥99.0%.

5. The pharmaceutically active composition according to claim 3, characterized in that The content of hydroxybutylphthalide is greater than zero and does not exceed 1.0% at most; preferably greater than zero and does not exceed 0.5%; more preferably greater than zero and does not exceed 0.1%.

6. The pharmaceutically active composition according to claim 3, characterized in that The content of any one of the alkenylphthalide or alkylphthalide does not exceed 0.1%.

7. The pharmaceutically active composition according to claim 3, characterized in that The butylphthalide derivative is selected from: (1) hydroxybutylphthalide; (2) optionally, one or two of butylphthalide and propylphthalide.

8. A pharmaceutical preparation, characterized in that The pharmaceutical preparation comprises the pharmaceutically active composition according to any one of claims 3 to 7 and a pharmaceutically acceptable carrier; optionally, the pharmaceutical composition further comprises other therapeutic components.

9. The pharmaceutical preparation according to claim 8, characterized in that The pharmaceutical preparation is an oral preparation or an injectable preparation. Preferably, the oral preparation comprises an oral solution, a tablet, a soft capsule, a sustained-release tablet or a dripping pill; the injectable preparation is preferably an injectable solution, a small water injection, a freeze-dried powder injection or an intravenous emulsion.

10. Use of the pharmaceutically active butylphthalide composition according to any one of claims 3 to 7, or the pharmaceutical preparation according to any one of claims 8 to 9, in the preparation of a drug for treating mild to moderate acute ischemic stroke.

Images