CN115554289A - Pharmaceutical active composition containing butylphthalide and preparation method thereof - Google Patents
Pharmaceutical active composition containing butylphthalide and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition containing butylphthalide and a preparation method thereof, wherein the pharmaceutical composition consists of butylphthalide and derivatives of butylphthalide, wherein the derivatives of butylphthalide comprise hydroxy butylphthalide, and optionally comprise one or more of butylphthalide and propylphthalide. The pharmaceutical composition can be used for treating mild and moderate acute ischemic stroke, has stable quality, remarkably improves side effects such as anorexia caused by abdominal discomfort, and can improve clinical curative effect and medication safety of butylphthalide preparation.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical active composition containing butylphthalide and butylphthalide derivatives and a preparation method thereof.
Background
The butylphthalide is 3-butyl-l (H) -isobenzofuranone, is racemic-3-n-butylphthalide, is also called apigenin, is firstly extracted from celery seeds, is colorless or light yellow clear oily liquid, has specific aroma, and is easy to degrade under the conditions of illumination and high temperature. The structure of butylphthalide is as follows:
since butylphthalide is firstly approved in the market in 2005 to date, the varieties on the market still remain embepr in Shiyao group, namely butylphthalide soft capsules and butylphthalide sodium chloride injection, and are used for treating light and moderate acute ischemic stroke. In phase II and phase III clinical studies of butylphthalide, adverse reactions mainly include mild to excessive increase of aminotransferase, occasional nausea, abdominal discomfort, mental symptoms and the like. The applicant develops mass comparison research on Enbipod and finds that the chromatogram of related substances has more impurity peaks; according to the patent information disclosure content of the Chinese marketed drug patent information registration platform, the butylphthalide soft capsule and the butylphthalide sodium chloride injection both disclose the patent ZL 201210184391.8 with the invention name of a butylphthalide pharmaceutical active composition and a preparation method thereof, and simultaneously claim the pharmaceutical composition containing the active ingredients of the patent claims 1 to 12; according to the description of the patent, the butylphthalide pharmaceutical active composition comprises more than ten kinds of alkenyl phthalides and alkyl phthalides, the key points comprise derivatives of butylphthalide such as butylphthalide, amylene phthalide, phthalide and propyl phthalide, and the content of the derivatives of single butylphthalide is far more than 0.1%; specifically, the content of any component of the alkenyl phthalide impurities can reach 0.5 percent at most, and the content of any component of the alkyl phthalide impurities can reach 1.0 percent at most. In addition, a plurality of prior arts and forced degradation tests of butylphthalide show that the main degradation impurity of butylphthalide is hydroxy butylphthalide, but the impurity is not controlled by the bulk drug and the preparation in the prior art. Therefore, the composition of the pharmaceutical active composition of butylphthalide is optimized, the content of butylphthalide derivatives is controlled, adverse reactions are reduced, and the medication safety is improved, so that the pharmaceutical active composition has clinical significance.
Disclosure of Invention
In view of the above, in order to solve at least one of the above technical problems, the present invention provides a pharmaceutical active composition containing butylphthalide and derivatives of butylphthalide and a preparation method thereof.
The invention provides a pharmaceutically active composition, which comprises butylphthalide and derivatives of butylphthalide, wherein the derivatives of butylphthalide comprise hydroxybutylphthalide.
Further, the derivatives of butylphthalide may further comprise either or both of alkenylphthalide and alkylphenthalide.
Further, the above alkenyl phthalide is selected from any one or more of methylene phthalide, vinyl phthalide, propylene phthalide, butylene phthalide and pentene phthalide; the above alkyl phthalide is selected from one or more of phthalide, methyl phthalide, ethyl phthalide, propyl phthalide, and amyl phthalide.
The structure of the derivatives of butylphthalide is as follows:
furthermore, the content of butylphthalide in the medicinal active composition is more than or equal to 98.0 percent, the content of butylphthalide derivatives is more than 0 and less than or equal to 2.0 percent, wherein the content of hydroxybutylphthalide is not more than 1.0 percent at most, and the content of any other butylphthalide derivatives is not more than 0.1 percent at most; preferably, the content of butylphthalide in the pharmaceutical active composition is more than or equal to 99.0%, the content of butylphthalide derivatives is more than 0 and less than or equal to 1.0%, wherein the content of hydroxybutylphthalide is no more than 0.5% at most, and the content of any other butylphthalide derivatives is no more than 0.1% at most.
Furthermore, the content of butylphthalide in the medicinal active composition is more than or equal to 98.5 percent, the content of butylphthalide derivatives is more than 0 and less than or equal to 1.5 percent, wherein the content of hydroxybutylphthalide is not more than 1.0 percent at most, and the content of any other butylphthalide derivatives is not more than 0.1 percent at most; preferably, the content of butylphthalide in the pharmaceutical active composition is more than or equal to 99.5 percent, the content of butylphthalide derivatives is more than 0 and less than or equal to 0.5 percent, wherein the content of hydroxybutylphthalide is not more than 0.2 percent at most, and the content of any other butylphthalide derivatives is not more than 0.1 percent at most; more preferably, the content of butylphthalide in the pharmaceutical active composition is more than or equal to 99.5%, the content of butylphthalide derivatives is more than 0 and less than or equal to 0.5%, wherein the content of hydroxybutylphthalide is no more than 0.2% at most, and the content of any other butylphthalide derivatives is no more than 0.05% at most.
Further, the derivatives of butylphthalide are selected from one or more of hydroxybutylphthalide, butylphthalide and propylphthalide.
Preferably, the derivatives of butylphthalide are selected from hydroxybutylphthalide, and optionally, the derivatives of butylphthalide further include any one or both of butylphthalide and propylphthalide.
The invention provides a preparation method of any one of the above pharmaceutical active compositions, which comprises the following steps:
A. opening a ring of lactone: adding the crude butylphthalide product into an alcohol solvent at room temperature, adding strong base while stirring, refluxing, stirring and reacting completely, cooling to room temperature, adding methyl tert-butyl ether, keeping the temperature at 5 +/-5 ℃, stirring and precipitating a solid for 2-5 h, performing suction filtration and washing to obtain a filter cake, and drying to obtain lactone ring-opening product carboxylate;
B. acid washing: adding the lactone ring-opening product carboxylate into water at room temperature, stirring for dissolving, adding weak acid to adjust the pH of the solution to acidity, separating out solids, and filtering to obtain a lactone ring-opening product;
C. lactone ring closure: adding the lactone ring-opening product into water at room temperature, stirring and dissolving, adding concentrated hydrochloric acid, heating to 40 +/-10 ℃, stirring and reacting for 3-5 h, adding methyl tert-butyl ether at room temperature for extraction, washing an organic phase with aqueous alkali and water, drying and concentrating to obtain an oily substance, namely a butylphthalide semi-crude product;
D. and (3) refining butylphthalide: and carrying out reduced pressure distillation on the butylphthalide semi-crude product by using an oil pump, and collecting fractions at 150-200 ℃ to obtain the butylphthalide medicinal active composition.
Further, a method for preparing any one of the above pharmaceutically active compositions, comprising the steps of:
A. opening a ring of lactone: adding the crude butylphthalide product into an alcohol solvent with the mass ratio of 2-10 times at room temperature, adding 1.0-2.0 molar equivalent of strong base while stirring, refluxing, stirring and reacting completely, cooling to room temperature, adding 6-15 times of methyl tert-butyl ether, keeping the temperature at 5 +/-5 ℃, stirring and precipitating a solid for 2-5 hours, performing suction filtration and washing to obtain a filter cake, and drying to obtain lactone ring-opening product carboxylate;
B. acid washing: adding the lactone ring-opening product carboxylate into water with the mass ratio of 6-15 times at room temperature, stirring and dissolving, adding weak acid to adjust the pH of the solution to acidity, separating out solid, and filtering to obtain the lactone ring-opening product;
C. lactone ring closure: adding the lactone ring-opening product into water with the mass ratio of 2-8 times at room temperature, stirring and dissolving, adding 0.1-2.0 molar equivalent of concentrated hydrochloric acid, heating to 40 +/-10 ℃, stirring and reacting for 3-5 h, adding methyl tert-butyl ether at room temperature for extraction, washing an organic phase with an alkali solution and water, drying and concentrating to obtain an oily substance, namely a butylphthalide semi-crude product;
D. and (3) refining butylphthalide: and carrying out reduced pressure distillation on the butylphthalide semi-crude product by using an oil pump, and collecting fractions at 150-200 ℃ to obtain the butylphthalide medicinal active composition.
Further, the amount of the weak acid used in the acid washing reaction in the step B is 1.2 to 5.0 molar equivalents to the built-in ring-opened carboxylate.
Further, in the above preparation method: the feeding ratios of the alcohol solvent, the strong base and the methyl tert-butyl ether relative to the crude butylphthalide product in the ring-opening reaction of the step A are respectively 2-10 times of mass ratio, 1.0-2.0 molar equivalent and 6-15 times of mass ratio, and the feeding ratios of water and weak acid relative to the lactone ring-opening product carboxylate in the acid-washing reaction of the step B are respectively 6-15 times of mass ratio and 1.2-5.0 molar equivalent; and C, in the ring closing reaction in the step C, the feeding ratios of water and concentrated hydrochloric acid relative to the lactone ring-opening substance are respectively 2-8 times of mass ratio and 0.1-2.0 molar equivalents.
Further, in any of the above preparation methods, the alcoholic solvent of step a comprises methanol, ethanol, propanol, isopropanol or tert-butanol, and the strong base comprises sodium hydroxide, potassium hydroxide; the weak acid of step B comprises citric acid, tartaric acid or acetic acid; the alkali solution in step C comprises saturated sodium bicarbonate water solution, 1-10% sodium hydroxide water solution or 1-10% potassium hydroxide water solution. Wherein, "%" is mass%.
Further, in step D of any of the above production methods, it is preferable to collect a fraction at 150 to 180 ℃.
In particular, the mass ratio or molar equivalent of the synthesis process of the present invention is the ratio of the materials in each step to the starting materials in the corresponding step.
The present invention provides a pharmaceutical formulation comprising a pharmaceutically active composition of any of the above and a pharmaceutically acceptable carrier, optionally in the presence of other therapeutic ingredients.
Furthermore, the pharmaceutical preparation is an oral preparation, preferably an oral solution, a tablet, a soft capsule, a sustained-release tablet or a dropping pill.
Furthermore, the medicinal preparation is an injection preparation, and preferably injection, small water injection, freeze-dried powder injection or intravenous emulsion.
The invention also provides an application of any one of the butylphthalide pharmaceutical active compositions or any one of the butylphthalide pharmaceutical compositions in preparation of medicines for treating light and moderate acute ischemic stroke diseases.
Advantageous effects: on one hand, the butylphthalide medicinal active composition optimizes the composition of the butylphthalide derivative, meets the medicinal requirements in all indexes, has stable quality in the placement process, and can improve gastrointestinal side reactions such as abdominal discomfort and the like caused by butylphthalide in the prior art, so that the butylphthalide medicinal active composition has less adverse reaction and stable property and meets more clinical requirements. On the other hand, the preparation method of the butylphthalide pharmaceutically active composition provided by the invention adopts a 'lactone ring opening-acid cleaning-lactone ring closing-distillation refining' process, so that the side reaction is less, the impurities are controllable, the production period is short, the energy is saved, the environment is protected, and the method is suitable for large-scale production.
Detailed Description
The scheme of the present invention will be explained below with reference to test examples and examples. It will be appreciated by those skilled in the art that the following examples are illustrative only and should not be taken as limiting the scope of the invention. The particular techniques or conditions not specified in the examples are performed according to the techniques or conditions described in the literature in the field or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products obtained commercially.
The content detection method of the components such as the derivatives of butylphthalide and butylphthalide comprises the following steps: measuring by high performance liquid chromatography
Chromatographic conditions and system adaptability test: 5-fluorophenylpropyl bonded silica gel is used as a filling agent; using 10mmol/L potassium dihydrogen phosphate solution (pH value is adjusted to 3.0 by phosphoric acid) as a mobile phase A, isopropanol: methanol: acetonitrile (5; the detection wavelength is 230nm; the sample introduction volume was 10. Mu.l, the flow rate was 1.0ml/min, and the column temperature was 35 ℃.
The gradient elution procedure was as follows:
test solution: taking a proper amount of butylphthalide sample, precisely weighing, adding acetonitrile to dissolve, quantitatively diluting to prepare a solution containing about 1.0mg of butylphthalide in each lml, taking 20 mu l of the solution of the test sample, injecting the solution of the test sample into a liquid chromatograph, recording a chromatogram until all peaks are completely discharged, and calculating the content of each component by an area normalization method.
Comparative example 1: a butylphthalide pharmaceutically active composition was prepared according to patent CN102716121B example 6.
Comparative example 2: high purity butylphthalide was prepared according to patent CN111961018B example 1.
Comparative example 3: butylphthalide pharmaceutical active composition
(1) Opening a ring of lactone: adding 1kg of crude butylphthalide into 5kg (5 times of mass ratio) of methanol at room temperature, adding 0.59kg of potassium hydroxide (2.0 molar equivalent) under stirring, refluxing and stirring to react completely, cooling to room temperature, adding 10kg (10 times of mass ratio) of methyl tert-butyl ether, keeping the temperature at 5 +/-5 ℃, stirring to separate out solid for 3 hours, performing suction filtration, washing with methyl tert-butyl ether to obtain a filter cake, and drying the filter cake at 55 +/-5 ℃ to constant weight to obtain the lactone ring-opening product carboxylate.
(2) Lactone ring closure: adding 1kg of lactone ring-opening product carboxylate into 10kg (10 times of mass ratio) of water at room temperature, stirring and dissolving, adding concentrated hydrochloric acid to enable the pH value of the solution to be 2.5, heating to 40 +/-5 ℃, stirring and reacting for 3-4 h, wherein no solid is found in a reaction system; adding methyl tert-butyl ether for extraction twice at room temperature, combining organic phases, washing once by using 1% sodium hydroxide aqueous solution, finally washing once by using water, drying by using anhydrous sodium sulfate, and concentrating to dryness to obtain an oily substance, namely a butylphthalide semi-crude product.
(3) And (3) refining butylphthalide: and carrying out reduced pressure distillation on the butylphthalide semi-crude product by using an oil pump, and collecting fractions at 150-200 ℃ to obtain the butylphthalide medicinal active composition.
Example 1: butylphthalide pharmaceutical active composition
A. Opening a ring of lactone: adding 1kg of crude butylphthalide into 8kg (8 times of mass ratio) of isopropanol at room temperature, adding 0.41kg of potassium hydroxide (1.4 molar equivalent) under stirring, refluxing, stirring and reacting completely, cooling to room temperature, adding 10kg (10 times of mass ratio) of methyl tert-butyl ether, keeping the temperature at 5 +/-5 ℃, stirring and precipitating solids for 3 hours, performing suction filtration, washing with methyl tert-butyl ether to obtain a filter cake, and drying the filter cake at 55 +/-5 ℃ to constant weight to obtain the lactone ring-opening product carboxylate.
B. Acid washing: adding 1kg of lactone ring-opening compound carboxylate into 10L (10 times of mass ratio) of water at room temperature, stirring for dissolving, adjusting the pH of the solution to acidity by using 1.72kg of citric acid (2.2 molar equivalents), precipitating a solid, and filtering to obtain the lactone ring-opening compound.
C. Lactone ring closure: adding 0.81kg of lactone ring-opening product into 2.43kg (3 times of mass ratio) of water at room temperature, stirring and dissolving, adding 0.38kg (1.0 molar equivalent) of concentrated hydrochloric acid, heating to 40 +/-5 ℃, stirring and reacting for 3-4 h, wherein no solid is found in a reaction system; adding methyl tert-butyl ether for extraction twice at room temperature, combining organic phases, washing once by using 1% sodium hydroxide aqueous solution, finally washing once by using water, drying by using anhydrous sodium sulfate, and concentrating to dryness to obtain an oily substance, namely a butylphthalide semi-crude product.
D. And (3) refining butylphthalide: and (3) carrying out reduced pressure distillation on the butylphthalide semi-crude product by using an oil pump, and collecting fractions at 150-180 ℃ to obtain the butylphthalide medicinal active composition.
Example 2: butylphthalide pharmaceutical active composition
A. Opening a ring of lactone: adding 1kg of crude butylphthalide into 2kg (2 times of mass ratio) of methanol at room temperature, adding 0.58kg of potassium hydroxide (2.0 molar equivalent) under stirring, refluxing and stirring to react completely, cooling to room temperature, adding 15kg (15 times of mass ratio) of methyl tert-butyl ether, keeping the temperature at 5 +/-5 ℃, stirring to separate out solid for 5 hours, performing suction filtration, washing with methyl tert-butyl ether to obtain a filter cake, and drying the filter cake at 55 +/-5 ℃ to constant weight to obtain the lactone ring-opening product carboxylate.
B. Acid washing: at room temperature, 1kg of lactone ring-opening product carboxylate is added into 6L (6 times of mass ratio) of water, stirred and dissolved, the pH of the solution is adjusted to acidity by 0.29kg of acetic acid (about 1.2 molar equivalent), solid is precipitated, and the lactone ring-opening product is obtained by filtration.
C. Lactone ring closure: adding 0.77kg of lactone ring-opening compound into 2kg (2 times of mass ratio) of water at room temperature, stirring for dissolving, adding 0.038kg (0.1 molar equivalent) of concentrated hydrochloric acid, heating to 45 +/-5 ℃, stirring for reacting for 3-4 h, wherein no solid is found in a reaction system; adding methyl tert-butyl ether at room temperature, extracting twice, combining organic phases, washing once with saturated sodium bicarbonate water solution, washing once with water, drying with anhydrous sodium sulfate, and concentrating to dryness to obtain an oily substance, namely a butylphthalide semi-crude product.
D. And (3) refining butylphthalide: and carrying out reduced pressure distillation on the crude butylphthalide product by an oil pump, and collecting 150-200 ℃ fractions to obtain the butylphthalide medicinal active composition.
Example 3: butylphthalide pharmaceutical active composition
A. Opening a ring of lactone: adding 1kg of crude butylphthalide into 10kg (10 times of mass ratio) of isopropanol at room temperature, adding 0.29kg of potassium hydroxide (1.0 molar equivalent) under stirring, refluxing, stirring and reacting completely, cooling to room temperature, adding 6kg (6 times of mass ratio) of methyl tert-butyl ether, keeping the temperature at 5 +/-5 ℃, stirring and precipitating solids for 3 hours, performing suction filtration, washing with methyl tert-butyl ether to obtain a filter cake, and drying the filter cake at 55 +/-5 ℃ to constant weight to obtain the lactone ring-opening product carboxylate.
B. Acid washing: adding 1kg of lactone ring-opening product carboxylate into 15L (15 times of mass ratio) of water at room temperature, stirring for dissolving, adjusting the pH of the solution to acidity by using 2.35kg (about 3.0 molar equivalent) of citric acid, precipitating a solid, and filtering to obtain the lactone ring-opening product.
C. Lactone ring closure: adding 0.83kg of lactone ring-opening product into 8kg (8 times of mass ratio) of water at room temperature, stirring and dissolving, adding 0.76kg (2.0 molar equivalent) of concentrated hydrochloric acid, heating to 35 +/-5 ℃, stirring and reacting for 3-4 h, wherein no solid is found in a reaction system; adding methyl tert-butyl ether for extraction twice at room temperature, combining organic phases, washing once by using 1% sodium hydroxide aqueous solution, finally washing once by using water, drying by using anhydrous sodium sulfate, and concentrating to dryness to obtain an oily substance, namely a butylphthalide semi-crude product.
D. And (3) refining butylphthalide: and (3) carrying out reduced pressure distillation on the butylphthalide semi-crude product by using an oil pump, and collecting fractions at 150-180 ℃ to obtain the butylphthalide medicinal active composition.
Example 4: butylphthalide pharmaceutical active composition
A. Opening a ring of lactone: adding 1kg of crude butylphthalide into 5kg (5 times of mass ratio) of ethanol at room temperature, adding 0.41kg of sodium hydroxide (1.4 molar equivalent) under stirring, refluxing and stirring for complete reaction, cooling to room temperature, adding 10kg (10 times of mass ratio) of methyl tert-butyl ether, keeping the temperature at 5 +/-5 ℃ and stirring for precipitating a solid for 2 hours, performing suction filtration, washing with methyl tert-butyl ether to obtain a filter cake, and drying the filter cake at 55 +/-5 ℃ to constant weight to obtain the lactone ring-opening product carboxylate.
B. At room temperature, adding 1kg of lactone ring-opening product carboxylate into 10kg (10 times of mass ratio) of water, stirring and dissolving, adjusting the pH of the solution to acidity by 1.21kg of acetic acid (5.0 molar equivalent), precipitating solids, and filtering to obtain the lactone ring-opening product.
C. Lactone ring closure: adding 0.86kg of lactone ring-opening product into 5kg (5 times of mass ratio) of water at room temperature, stirring for dissolving, adding 0.41kg of concentrated hydrochloric acid (1.0 molar equivalent), heating to 40 +/-5 ℃, stirring for reacting for 4-5 h, wherein no solid is found in a reaction system; adding methyl tert-butyl ether for extraction twice at room temperature, combining organic phases, washing once by using 10% sodium hydroxide aqueous solution, finally washing once by using water, drying by using anhydrous sodium sulfate, and concentrating to dryness to obtain an oily substance, namely a butylphthalide semi-crude product.
D. And (3) refining butylphthalide: and carrying out reduced pressure distillation on the butylphthalide semi-crude product by using an oil pump, and collecting fractions at 160-180 ℃ to obtain the butylphthalide medicinal active composition.
Test example 1: quality study of butylphthalide pharmaceutical active composition
Accelerated stability tests (40 ℃ C. + -. 2 ℃ C.; RH:75% + -. 5%) were conducted on the butylphthalide samples of examples 1-4 and comparative example 3, according to the guidelines associated with stability testing. The results are shown in Table 1.
Remarking: (1) The derivatives of butylphthalide refer to hydroxybutylphthalide, alkenylphthalide (including cis-trans isomers, such as methamphthalide, vinylphthalide, propenylphthalide, butenylphthalide, pentenylphthalide), and alkylphenylphthalides (such as phthalide, methylphthalide, ethylphthalide, propylphthalide, pentylphthalide), and butylphthalide derivatives not listed in the above table are not detected in the samples; (2) The other largest single impurities mentioned above are other known and unknown impurities besides the butylphthalide derivative.
The 6-month accelerated stability test results for the above-listed butylphthalide samples show: the total impurities of the samples of the embodiments 1 to 4 of the invention increase by about 0.1%, and the content of butylphthalide is reduced by about 0.1%, which proves that the quality of the butylphthalide medicinal active composition of the embodiments of the invention is stable; while the total hetero increase of the comparative example 3 exceeds 0.7%, and the content of the butylphthalide is reduced by more than 0.7%, which proves that the butylphthalide pharmaceutically active composition of the comparative example 3 is relatively unstable. Accordingly, it can be concluded that when the content of butylphthalide 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%, wherein 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 stabilized; particularly, when the content of butylphthalide in the pharmaceutical active composition of butylphthalide is not less than 99.5%, the content of total butylphthalide derivatives is not more than 0.5%, wherein 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 acceleration stability is better.
The characteristics and advantages of the synthesis process of the invention are summarized as follows by combining the prior art: (1) The process of the invention can well remove various impurities, in particular the derivatives of butylphthalide. (2) The ring-opening post-treatment of the invention adopts weak acid pickling, and only the solution needs to be controlled to reach an acid environment without rigor controlling the pH value to be in a precise range; in addition, compared with the processes of salt recrystallization and the like in the prior art, the acid washing operation steps have the advantages of few process links, simplicity in operation and material and production time saving. (3) The acid washing can reduce the dosage of concentrated hydrochloric acid in the subsequent ring closing reaction, greatly reduce the risk of impurity generation and prevent the corrosion risk of equipment to a higher degree. (4) The stirring solid-separating temperature in the ring-opening step and the reaction temperature in the ring-closing step are both room temperature, and compared with the high-temperature or low-temperature reaction conditions in the prior art, the method has the advantages of low equipment requirement and lower energy consumption; in addition, the ring closing reaction of the invention can be completed in 3 to 5 hours, which is far lower than the dozens of hours in the prior art, thereby greatly shortening the production period. In conclusion, the preparation process of the butylphthalide medicinal active composition is suitable for large-scale production, short in production period, energy-saving, green and environment-friendly, few in impurities, and stable and controllable in product quality.
Example 5: butylphthalide oral solution
The raw material medicaments: the butylphthalide pharmaceutically active composition prepared in example 1;
the prescription composition is as follows:
the preparation method comprises the following steps: weighing hydroxypropyl-beta-cyclodextrin and sodium citrate with the prescription amount, adding purified water accounting for 60 percent of the total volume at the temperature of 75-80 ℃, stirring until the mixture is completely dissolved, adding butylphthalide with the prescription amount, stirring for 90min at the temperature of 75-80 ℃, and cooling to 25-30 ℃ after the solution is completely dissolved; fixing the volume of purified water, and adjusting the pH value of the solution to 4.0 by 10% (w/v) citric acid; filtering with 0.8 μm filter membrane, and packaging according to 100 pieces; sterilizing at 121 deg.C for 15min.
Example 6: butylphthalide oral solution
The raw material medicaments: the butylphthalide pharmaceutically active composition prepared in example 3;
the formulation and preparation were the same as in example 5.
Example 7: butylphthalide oral solution
The raw material medicaments comprise: the butylphthalide pharmaceutically active composition prepared in example 4;
the formulation and preparation were the same as in example 5.
Example 8: butylphthalide sodium chloride injection
The raw material medicaments: the butylphthalide pharmaceutically active composition prepared in example 1;
the prescription composition is as follows:
the preparation method comprises the following steps: taking the prescription amount of purified water, boiling and cooling to 80 ℃. 80g of sulfobutyl-beta-cyclodextrin sodium (the substitution degree is 6.2-6.9, the average substitution degree is 6.4, the molecular weight is 2145.2 g/mol) and 90g of sodium chloride are weighed and added into 8L of purified water with the temperature of 80 ℃ to be stirred to be completely dissolved. Weighing 2.5g of butylphthalide, adding into a sulfobutyl-beta-cyclodextrin sodium solution, and stirring for 90min at 80 ℃ in an oil bath to completely dissolve. Cooling to room temperature, adding 0.2M hydrochloric acid solution to adjust pH to 4.5, and adding purified water to 10L. Filtering with a circulating water type multi-purpose vacuum pump through a 0.45 μm filter membrane. The prepared solution is filled according to 100ml per bottle. After filling, the mixture was sterilized at 121 ℃ for 15 minutes to obtain an example sample.
Example 9: butylphthalide small water needle
The raw material medicaments: the butylphthalide pharmaceutically active composition prepared in example 3;
the prescription composition is as follows:
the preparation method comprises the following steps: weighing butylphthalide and HS-15 according to the prescription amount, and stirring for 90-120 minutes at 60-70 ℃ to completely dissolve the butylphthalide; cooling to 25-30 ℃, adding purified water, stirring and mixing, and fixing the volume to the total volume; adjusting the pH value of the solution to 4.0 by 1mol/L hydrochloric acid solution; filtering with 0.45 μm filter membrane, packaging according to 180 pieces (10 ml/piece), and sterilizing at 121 deg.C for 15 min; the whole process is protected by nitrogen filling.
Example 10: butylphthalide venous emulsion
The raw material medicaments: the butylphthalide pharmaceutically active composition prepared in example 3;
the prescription composition and the preparation method are the same as in example 14 of patent CN 102716121A.
Example 11: butylphthalide soft capsule
The raw material medicaments comprise: the butylphthalide pharmaceutically active composition prepared in example 1;
the prescription composition and the preparation method are the same as in example 10 of patent CN 102716121A.
Comparative example 4: butylphthalide soft capsules are commercially available (batch number: 1182201102).
Comparative example 5: butylphthalide sodium chloride injection (batch number 6182007106) is commercially available.
Comparative example 6: butylphthalide oral solution
The raw material medicaments: the butylphthalide pharmaceutically active composition prepared in comparative example 3;
the formulation and preparation were the same as in example 5.
Test 2: stability study of butylphthalide pharmaceutical composition
Accelerated stability tests (40 ℃ C. + -. 2 ℃ C.; RH:75% + -. 5%) were conducted on the butylphthalide formulations of examples 5-11 and comparative examples 4-6, according to the guidelines for stability testing. The results are shown in tables 2 and 3.
As can be seen from the above table: in an accelerated test of 6 months, the number and content of the relevant substances of the butylphthalide preparations of examples 5 to 11 are stable, and the content of butylphthalide is also stable, which proves 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 proves that the butylphthalide pharmaceutically active composition of the present invention has strong compatibility of the auxiliary materials. In the accelerated test of 6 months, the total impurity growth amplitude of the comparative example 4 and the comparative example 5 is larger, the number of impurities is obviously more than that of the preparation of the embodiment of the invention, particularly, the total impurity content of the commercial soft capsule of the comparative example 4 exceeds 1.0 percent, the total impurities are increased, and the number of the impurities is close to 20, which is much higher than that of the preparation of the embodiment of the invention. Therefore, the results of comparing 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 if the butylphthalide pharmaceutically active composition is stable, the obtained butylphthalide pharmaceutically active composition is stable, i.e. the stability of the butylphthalide pharmaceutically active composition affects the stability of the pharmaceutical formulation, and accordingly, when the content of butylphthalide in the butylphthalide pharmaceutically active composition is not less than 98.0%, and the content of butylphthalide derivatives is not more than 2.0%, wherein the content of hydroxybutylphide is not more than 1.0%, and the content of any other butylphthalide derivatives is not more than 0.1%, the stable butylphthalide pharmaceutically active composition and the stable butylphthalide pharmaceutically active composition can be obtained.
Test example 3: acute toxicity test of single administration for rats and mice
A driving test sample: comparative example 1, comparative example 3, example 2, example 3, example 4.
Processing a capsule wall-carried sample: putting the materials into a clean administration container, adding a proper amount of Solutol for dissolving, performing vortex oscillation, adding pure water, performing ultrasonic treatment, and performing vortex oscillation until the compound is completely dissolved (the compound is ready for use).
⒊ Experimental:
(1) Single dose toxicity test in rats: a plurality of healthy adult SD rats with the weight of 150 to 160g and half male and female are taken, animals are randomly divided into a plurality of groups, and 10 rats in each group are subjected to single-dose toxicity tests by adopting a half lethal dose method for comparative example 1, comparative example 3, example 2, example 3 and example 4 in the patent of the invention. All animals were fasted and had free access to water 12h prior to dosing. On the day of administration, each administration group is administered with corresponding drug via intragastric administration with intragastric volume of 5ml/kg, rats are observed for toxic reaction and death within 7 days after single administration, and LD is calculated 50 The value is obtained.
(2) Single dose toxicity test in mice: taking a plurality of healthy adult ICR mice with the weight of 18 to 22g and half of each mouse, and randomly dividing the mice into a plurality of groupsFor 10 mice per group, toxicity tests were performed by single administration using the "median lethal method" for comparative example 1, comparative example 3, example 2, example 3, and example 4 in the patent of the present invention. All animals were fasted and had free access to water 12h prior to dosing. On the administration day, each administration group is intragastrically administered with corresponding medicine, the intragastrically administered volume is 0.1ml/10g, the toxic reaction and death condition of mice are observed within 7 days after single administration, and LD is calculated 50 The value is obtained.
⒋ experimental results:
from the above results, it appears that: the LD50 value of the butylphthalide pharmaceutical active composition of the example 2-4 of the invention is obviously higher than that of the comparative example 1 and 3 no matter in rats and mice, which shows that the toxicity of the butylphthalide pharmaceutical active composition of the example after single administration is lower than that of the comparative example 1 and 3, wherein the butylphthalide pharmaceutical active composition of the example 3 has the best safety.
Test example 4: effect of continuous administration in rats on general State and food intake
Soil conveying appliance test purpose
Examplesthe effect of each compound on the food intake of rats after continuous gavage administration for 14 days in rats was examined, and the effect of each compound on the gastrointestinal tract of rats was indirectly evaluated.
Capsule wall testing and preparation thereof
(1) And (3) testing a sample: example 1, example 2, example 3, example 4, comparative example 1, comparative example 2, comparative example 3, comparative example 4.
(2) Sample treatment: putting the materials into a clean administration container, adding a proper amount of Solutol for dissolving, carrying out spiral oscillation, adding pure water, carrying out ultrasonic treatment, and carrying out spiral oscillation until the compound is completely dissolved (for use in preparation).
⒊ test grouping and dosing
⒋ test method
The SD rats are male and female simultaneously and are randomly grouped into 10 rats each group; the effect of the drug on the food intake of rats was observed and recorded after 14 consecutive days, once daily, by gavage of the corresponding drug or vehicle.
⒌ test results
As seen from the table above, compared with the blank group, the food intake of the rats in the groups of examples 1-4 within 24 hours after the last administration is basically consistent with that of the blank group, and no statistical difference exists; compared with the blank group, the rats in the groups of comparative examples 1-4 have extremely obviously reduced food intake within 24 hours after the last administration, and have statistical difference (P < 0.01); the butylphthalide medicinal active composition of the invention is proved to be capable of obviously reducing the side reactions such as gastrointestinal discomfort and the like.
The above description is only a preferred embodiment of the present invention, and it should be noted that various modifications to these embodiments can be implemented by those skilled in the art without departing from the technical principle of the present invention, and these modifications should be construed as the scope of the present invention.
Claims (10)
1. A pharmaceutically active composition of butylphthalide, comprising butylphthalide and a derivative of butylphthalide, wherein said derivative of butylphthalide comprises hydroxybutylphthalide.
2. The pharmaceutically active composition according to claim 1, wherein the derivative of butylphthalide further comprises either or both of an alkenylphthalide or an alkylphthalide.
3. The pharmaceutically active composition according to claim 1, wherein the content of butylphthalide in the pharmaceutically active composition is not less than 98.0%, the content of butylphthalide derivative is not less than 2.0% and not more than 0%, wherein the content of hydroxybutylphthalide is not more than 1.0% at the highest, and any of the other butylphthalide derivatives is not more than 0.1% at the highest; preferably, the content of butylphthalide in the pharmaceutical active composition is more than or equal to 99.0 percent, the content of butylphthalide derivatives is more than 0 and less than or equal to 1.0 percent, wherein the content of hydroxybutylphthalide is not more than 0.5 percent at most, and the content of any other butylphthalide derivatives is not more than 0.1 percent at most.
4. The pharmaceutical active composition according to claim 1, wherein the derivatives of butylphthalide are selected from one or more of hydroxybutylphthalide, butylphthalide and propylphthalide.
5. A process for the preparation of a pharmaceutically active composition according to any one of claims 1 to 4, comprising the steps of:
A. opening a ring of lactone: adding the crude butylphthalide product into an alcohol solvent at room temperature, adding strong base while stirring, refluxing, stirring and reacting completely, cooling to room temperature, adding methyl tert-butyl ether, keeping the temperature at 5 +/-5 ℃, stirring and precipitating a solid for 2-5 h, performing suction filtration and washing to obtain a filter cake, and drying to obtain lactone ring-opening product carboxylate;
B. acid washing: adding the lactone ring-opening product carboxylate into water at room temperature, stirring for dissolving, adding weak acid to adjust the pH of the solution to acidity, separating out solids, and filtering to obtain a lactone ring-opening product;
C. lactone ring closure: adding the lactone ring-opening product into water at room temperature, stirring and dissolving, adding concentrated hydrochloric acid, heating to 40 +/-10 ℃, stirring and reacting for 3-5 h, adding methyl tert-butyl ether at room temperature for extraction, washing an organic phase with aqueous alkali and water, drying and concentrating to obtain an oily substance, namely a butylphthalide semi-crude product;
D. and (3) refining butylphthalide: and carrying out reduced pressure distillation on the butylphthalide semi-crude product by using an oil pump, and collecting fractions at 150-200 ℃ to obtain the butylphthalide medicinal active composition.
6. The method of claim 5, wherein the alcoholic solvent of step A comprises methanol, ethanol, propanol, isopropanol or tert-butanol, and the strong base comprises sodium hydroxide, potassium hydroxide; the weak acid of step B comprises citric acid, tartaric acid or acetic acid; the alkali solution in step C comprises saturated sodium bicarbonate water solution, 1-10% sodium hydroxide water solution or 1-10% potassium hydroxide water solution.
7. A pharmaceutical formulation comprising a pharmaceutically active composition according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier, optionally in the presence of other therapeutic ingredients.
8. Pharmaceutical preparation according to claim 7, characterized in that it is an oral preparation, preferably an oral solution, tablet, soft capsule, sustained release tablet or drop pill.
9. The pharmaceutical preparation according to claim 7, wherein the pharmaceutical preparation is an injection preparation, preferably an injection solution, a small water injection, a lyophilized powder injection or an intravenous emulsion.
10. The butylphthalide pharmaceutical active composition according to any one of claims 1 to 4, or the pharmaceutical composition according to any one of claims 7 to 9, for use in the preparation of a medicament for treating mild or moderate acute ischemic stroke diseases.
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| CN105130934A (en) * | 2015-08-15 | 2015-12-09 | 石药集团恩必普药业有限公司 | Butyl phthalide raw material drug product and preparation method thereof |
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