CN107970208B - Butylphthalide injection and preparation method thereof - Google Patents
Butylphthalide injection and preparation method thereof Download PDFInfo
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Abstract
The invention relates to butylphthalide injection and a preparation method thereof. The butylphthalide injection comprises butylphthalide or derivatives thereof, a surfactant and water for injection, wherein the surfactant is selected from one or more of phospholipid, polyethylene glycol-12-hydroxystearate, polyethylene glycol-VE carbonate, polyethylene glycol-VE succinate, polyethylene glycol-distearoyl phosphatidyl ethanolamine, polyethylene glycol-cholesterol succinate, polyethylene glycol-cholesterol methyl ester, polyethylene glycol-cholesterol sulfate, polyoxyethylene sorbitan fatty acid esters and poloxamer. The butylphthalide injection can effectively cover up the special fragrance of butylphthalide; the quality is stable; the butylphthalide has high content, can be subpackaged into small-volume preparations, can be used for intravenous injection and intramuscular injection, and meets the clinical administration requirement; the preparation process is simple, strong in operability and beneficial to industrialization.
Description
The application is a divisional application of an invention patent application with the application number of CN201210214131.0, the application date of 2012, 06, 27 and the invention name of 'a butylphthalide injection and a preparation method thereof'.
Technical Field
The invention belongs to the technical field of medicines, relates to a medicine injection and a preparation method thereof, and particularly relates to a butylphthalide injection and a preparation method thereof.
Background
Butylphthalide (3-n-butylphthalide, abbreviated as NBP), named 3-butyl-1 (H) -isobenzofuranone in its entirety, apigenin, is a racemate extracted from celery seeds, and can also be synthesized artificially. Butylphthalide is an oily liquid, is insoluble in water, has strong celery flavor, and contains a chiral carbon atom in a molecule, so that the butylphthalide exists in two optical isomers, namely levo-butylphthalide and dextro-butylphthalide. Butylphthalide can reduce the infarct focus after focal cerebral ischemia, increase cerebral blood flow in ischemic area, improve microcirculation in cerebral ischemic area, protect mitochondrial function, reduce damage degree of nerve function, improve energy metabolism in brain after global cerebral ischemia, etc., and act on multiple links of cerebral ischemia pathology. Chinese patents 98125618.X, 03137457.3, 200310100222.2 and 200410001748.X disclose the application of butylphthalide in antithrombotic and platelet aggregation resisting, and levo-butylphthalide in preventing and treating dementia, cerebral infarction and cerebral ischemia.
At present, products on the market of butylphthalide include soft capsules and infusion solutions. The soft capsule is an oral preparation, and although the preparation can cover up the special fragrance of the medicine, the purposes of quick medicine release and quick treatment effect cannot be achieved. The infusion solution adopts the cyclodextrin inclusion technology, and although the problem that the soft capsule cannot quickly release medicine is solved, the infusion solution can only be used for intravenous injection or drip infusion due to large volume, and the clinical medication requirement cannot be well met.
Chinese patent 200410012533.8 discloses a butylphthalide lyophilized powder for injection, which comprises butylphthalide, emulsifier and co-emulsifier, excipient and water for injection. Chinese patent 200510102355.2 discloses a butylphthalide intravenous emulsion, which is prepared from butylphthalide, oil, emulsifier, isotonic agent and water for injection by emulsifying by two-step emulsifying dispersion method. The two dosage forms increase the solubility of butylphthalide, increase the targeting property of butylphthalide brain tissue, and reduce its toxic and side effects. But the preparation process is complex and belongs to a non-thermal stable system, and the emulsion breaking phenomenon can occur to influence the product quality; in addition, the dosage form is still intravenous injection or instillation.
Chinese patent application 200610081440.X discloses a butylphthalide concentrated solution, which contains butylphthalide and at least one pharmaceutically acceptable carrier, wherein the carrier comprises: non-aqueous solvent, solubilizer, cosolvent, antioxidant and stabilizer. The preparation is compatible with glucose injection or sodium chloride injection when in use, is difficult to operate when diluted in clinical application, and is still intravenous injection or instillation.
In conclusion, the butylphthalide dosage form disclosed in the prior art has a complex process and unstable quality, and cannot well meet the clinical medication requirement.
Disclosure of Invention
In view of the problems in the prior art, the invention mainly aims to provide a butylphthalide injection which has small volume and simple preparation process and can be simultaneously used for intramuscular injection and intravenous injection and a preparation method thereof.
Therefore, the invention provides a butylphthalide injection, which comprises butylphthalide or derivatives thereof, a surfactant and water for injection.
Wherein:
the butylphthalide is racemic butylphthalide or levo-butylphthalide.
The weight ratio of the butylphthalide or the derivative thereof, the surfactant and the water for injection is as follows: 1: 2-50: 50-500, preferably: 1: 3-20: 80-400.
The surfactant is selected from: phospholipid, polyethylene glycol-12-hydroxystearate ester
HS 15), polyethylene glycol-VE carbonate, PEG-THS (polyethylene glycol-VE succinate), PEG-DSPE (polyethylene glycol-distearoylphosphatidylethanolamine), PEG-CHS (polyethylene glycol-cholesterol succinate), PEG-CHM (polyethylene glycol-cholesterol methyl ester), polyethylene glycol-cholesterol sulfate, polyoxyethylene sorbitan fatty acid esters (emetic type: tween), poloxamer. Further, the phospholipids include egg yolk lecithin, soybean lecithin, PC (phosphatidylcholine), EPG (egg phosphatidylglycerol), SPG (soybean phosphatidylglycerol), DOPC (dioleoylphosphatidylcholine), DOPG (dioleoylphosphatidylglycerol), DPPC (dipalmitoylphosphatidylcholine), DPPG (dipalmitoylphosphatidylglycerol), DMPC (dimyristoylphosphatidylcholine), DMPG (dimyristoylphosphatidylglycerol), DLPC (dilauroyl phosphatidylcholine), DLPG (dilauroyl phosphatidylglycerol); the molecular weight of polyethylene glycol in the polyethylene glycol-12-hydroxystearate, VE polyethylene glycol succinate, polyethylene glycol-VE carbonate, polyethylene glycol-VE succinate, polyethylene glycol-distearoyl phosphatidyl ethanolamine, polyethylene glycol-cholesterol succinate, polyethylene glycol-cholesterol methyl ester and polyethylene glycol-cholesterol sulfate (hereinafter referred to as polyethylene glycol surfactant for short) is 300-30000; the polyoxyethylene sorbitan fatty acid ester is tween 20, tween 40, tween 60, tween 65, tween 80 or tween 85; the Poloxamer is selected from Poloxamer122、Poloxamer 188、Poloxamer 237、Poloxamer 338、Poloxamer 407。
The structural formulas of the polyethylene glycol-12-hydroxystearate, the PEG-THS, the PEG-CHS and the PEG-CHM are as follows:
polyethylene glycol-12-hydroxystearate
PEG-THS
PEG-CHS
PEG-CHM
n-5 to 500(PEG molecular weight 300 to 30000)
Optionally, the butylphthalide injection further comprises a stabilizer of other components, a pH regulator and the like. The stabilizer comprises nitrogen, inert gas, antioxidant, tocopherol, vitamin C or EDTA-2 Na; the pH regulator comprises organic acid base and organic acid base, wherein the organic acid is selected from one or more of citric acid, lactic acid, fumaric acid, tartaric acid, gluconic acid, lactobionic acid, sorbic acid, succinic acid, maleic acid, oxalic acid, formic acid, acetic acid, benzenesulfonic acid, benzoic acid, glutamic acid, lysine, aspartic acid and the like; the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate and the like; the organic base is selected from one or more of ammonia water, pyridine, diethylamine, triethylamine, EDTA, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyl lithium, phenyl lithium, diisopropylamine Lithium (LDA), hexamethyldisilazane Lithium (LiHMDS) and the like, and the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, potassium phosphate and the like.
The butylphthalide injection can exist in a water injection form, and can also be prepared into a solid preparation by adopting a freeze-drying technology. Common lyoprotectants include, but are not limited to, maltose, mannitol, and glucose in combination, such as mannitol 6% in combination with glucose 1.5%, mannitol 6% in combination with glucose 3%, mannitol 6% in combination with maltose 1.5%, mannitol 2% in combination with glucose 4%, and maltose 8%.
In one embodiment of the invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, phospholipid and water for injection, and the weight percentage of each component is as follows by 100 mL:
preferably, the weight percentage of each component is as follows:
the phospholipid is selected from one or more of egg yolk lecithin, soybean lecithin, PC (phosphatidylcholine), EPG (egg phosphatidylglycerol), SPG (soybean phosphatidylglycerol), DOPC (dioleoylphosphatidylcholine), DOPG (dioleoylphosphatidylglycerol), DPPC (dipalmitoylphosphatidylglycerol), DMPC (dimyristoylphosphatidylcholine), DMPG (dimyristoylphosphatidylglycerol), DLPC (dilauroyl phosphatidylcholine), and DLPG (dilauroyl phosphatidylglycerol).
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, polyethylene glycol surfactant and water for injection, wherein the weight percentage of each component is as follows based on 100 mL:
preferably, the weight percentage of each component is as follows:
the polyethylene glycol surfactant is selected from: polyethylene glycol-12-hydroxystearate, polyethylene glycol-VE carbonate, PEG-THS (polyethylene glycol-VE succinate), PEG-DSPE (polyethylene glycol-distearoylphosphatidylethanolamine), PEG-CHS (polyethylene glycol-cholesterol succinate), PEG-CHM (polyethylene glycol-cholesterol methyl ester), polyethylene glycol-cholesterol sulfate, preferably polyethylene glycol-12-hydroxystearate or a combination thereof with other polyethylene glycol surfactants.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, polyoxyethylene sorbitan fatty acid ester and water for injection, wherein the weight percentage of each component is calculated by 100 mL:
preferably, the weight percentage of each component is as follows:
the polyoxyethylene sorbitan fatty acid ester is selected from: one or any combination of tween 20, tween 40, tween 60, tween 65, tween 80 and tween 85, preferably tween 80 or a combination thereof with other polyoxyethylene sorbitan fatty acid esters.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, poloxamer and water for injection, wherein the weight percentage of each component is calculated by 100 mL:
preferably, the weight percentage of each component is as follows:
the Poloxamer is selected from one of Poloxamer 122, Poloxamer188, Poloxamer 237, Poloxamer 338 and Poloxamer 407 or any combination thereof.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, phospholipid, polyethylene glycol surfactant and water for injection, wherein the weight percentage of each component is calculated by 100 mL:
preferably, the weight percentage of each component is as follows:
the phospholipid is selected from one or more of egg yolk lecithin, soybean lecithin, PC (phosphatidylcholine), EPG (egg phosphatidylglycerol), SPG (soybean phosphatidylglycerol), DOPC (dioleoylphosphatidylcholine), DOPG (dioleoylphosphatidylglycerol), DPPC (dipalmitoylphosphatidylglycerol), DMPC (dimyristoylphosphatidylcholine), DMPG (dimyristoylphosphatidylglycerol), DLPC (dilauroyl phosphatidylcholine), DLPG (dilauroyl phosphatidylglycerol); the polyethylene glycol surfactant is selected from: one or more of polyethylene glycol-12-hydroxystearate, polyethylene glycol-VE carbonate, PEG-THS (polyethylene glycol-VE succinate), PEG-DSPE (polyethylene glycol-distearoylphosphatidylethanolamine), PEG-CHS (polyethylene glycol-cholesterol succinate), PEG-CHM (polyethylene glycol-cholesterol methyl ester), and polyethylene glycol-cholesterol sulfate.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, polyethylene glycol surfactant, polyoxyethylene sorbitan fatty acid ester and water for injection, wherein the weight percentage of each component is calculated by 100 mL:
preferably, the weight percentage of each component is as follows:
the polyethylene glycol surfactant is selected from: one or more of polyethylene glycol-12-hydroxystearate, polyethylene glycol-VE carbonate, PEG-THS (polyethylene glycol-VE succinate), PEG-DSPE (polyethylene glycol-distearoylphosphatidylethanolamine), PEG-CHS (polyethylene glycol-cholesterol succinate), PEG-CHM (polyethylene glycol-cholesterol methyl ester), and polyethylene glycol-cholesterol sulfate; the polyoxyethylene sorbitan fatty acid ester is selected from: one or more of tween 20, tween 40, tween 60, tween 65, tween 80 and tween 85.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, phospholipid, polyoxyethylene sorbitan fatty acid ester and water for injection, wherein the weight percentage of each component is calculated by 100 mL:
preferably, the weight percentage of each component is as follows:
the phospholipid is selected from one or more of egg yolk lecithin, soybean lecithin, PC (phosphatidylcholine), EPG (egg phosphatidylglycerol), SPG (soybean phosphatidylglycerol), DOPC (dioleoylphosphatidylcholine), DOPG (dioleoylphosphatidylglycerol), DPPC (dipalmitoylphosphatidylglycerol), DMPC (dimyristoylphosphatidylcholine), DMPG (dimyristoylphosphatidylglycerol), DLPC (dilauroyl phosphatidylcholine), DLPG (dilauroyl phosphatidylglycerol); the polyoxyethylene sorbitan fatty acid ester is selected from: one or more of tween 20, tween 40, tween 60, tween 65, tween 80 and tween 85.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, phospholipid, poloxamer and water for injection, wherein the weight percentage of each component is calculated by 100 mL:
preferably, the weight percentage of each component is as follows:
the phospholipid is selected from one or more of egg yolk lecithin, soybean lecithin, PC (phosphatidylcholine), EPG (egg phosphatidylglycerol), SPG (soybean phosphatidylglycerol), DOPC (dioleoylphosphatidylcholine), DOPG (dioleoylphosphatidylglycerol), DPPC (dipalmitoylphosphatidylglycerol), DMPC (dimyristoylphosphatidylcholine), DMPG (dimyristoylphosphatidylglycerol), DLPC (dilauroyl phosphatidylcholine), DLPG (dilauroyl phosphatidylglycerol); the Poloxamer is selected from one or more of Poloxamer 122, Poloxamer188, Poloxamer 237, Poloxamer 338 and Poloxamer 407.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, polyethylene glycol surfactant, poloxamer and water for injection, wherein the weight percentage of each component is as follows based on 100 mL:
preferably, the weight percentage of each component is as follows:
the polyethylene glycol surfactant is selected from: one or more of polyethylene glycol-12-hydroxystearate, polyethylene glycol-VE carbonate, PEG-THS (polyethylene glycol-VE succinate), PEG-DSPE (polyethylene glycol-distearoylphosphatidylethanolamine), PEG-CHS (polyethylene glycol-cholesterol succinate), PEG-CHM (polyethylene glycol-cholesterol methyl ester), and polyethylene glycol-cholesterol sulfate; the Poloxamer is selected from one or more of Poloxamer 122, Poloxamer188, Poloxamer 237, Poloxamer 338 and Poloxamer 407.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, polyoxyethylene sorbitan fatty acid ester, poloxamer and water for injection, wherein the weight percentage of each component is as follows based on 100 mL:
preferably, the weight percentage of each component is as follows:
the polyoxyethylene sorbitan fatty acid ester is selected from: one or more of tween 20, tween 40, tween 60, tween 65, tween 80 and tween 85; the Poloxamer is selected from one or more of Poloxamer 122, Poloxamer188, Poloxamer 237, Poloxamer 338 and Poloxamer 407.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, polyethylene glycol surfactant, phospholipid, polyoxyethylene sorbitan fatty acid ester and water for injection, wherein the weight percentage of each component is calculated by 100 mL:
preferably, the weight percentage of each component is as follows:
the polyethylene glycol surfactant is selected from: one or more of polyethylene glycol-12-hydroxystearate, polyethylene glycol-VE carbonate, PEG-THS (polyethylene glycol-VE succinate), PEG-DSPE (polyethylene glycol-distearoylphosphatidylethanolamine), PEG-CHS (polyethylene glycol-cholesterol succinate), PEG-CHM (polyethylene glycol-cholesterol methyl ester), and polyethylene glycol-cholesterol sulfate; the phospholipid is selected from one or more of egg yolk lecithin, soybean lecithin, PC (phosphatidylcholine), EPG (egg phosphatidyl glycerol), SPG (soybean phosphatidyl glycerol), DOPC (dioleoyl phosphatidylcholine), DOPG (dioleoyl phosphatidyl glycerol), DPPC (dipalmitoyl phosphatidylcholine), DPPG (dipalmitoyl phosphatidyl glycerol), DMPC (dimyristoyl phosphatidylcholine), DMPG (dimyristoyl phosphatidyl glycerol), DLPC (dilauroyl phosphatidylcholine), DLPG (dilauroyl phosphatidyl glycerol), preferably egg yolk lecithin and soybean lecithin; the polyoxyethylene sorbitan fatty acid ester is selected from: one or more of tween 20, tween 40, tween 60, tween 65, tween 80 and tween 85.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, polyethylene glycol surfactant, poloxamer, polyoxyethylene sorbitan fatty acid ester and water for injection, wherein the weight percentage of each component is calculated by 100 mL:
preferably, the weight percentage of each component is as follows:
the polyethylene glycol surfactant is selected from: one or more of polyethylene glycol-12-hydroxystearate, polyethylene glycol-VE carbonate, PEG-THS (polyethylene glycol-VE succinate), PEG-DSPE (polyethylene glycol-distearoylphosphatidylethanolamine), PEG-CHS (polyethylene glycol-cholesterol succinate), PEG-CHM (polyethylene glycol-cholesterol methyl ester), and polyethylene glycol-cholesterol sulfate; the Poloxamer is selected from one or more of Poloxamer 122, Poloxamer188, Poloxamer 237, Poloxamer 338 and Poloxamer 407; the polyoxyethylene sorbitan fatty acid ester is selected from: one or more of tween 20, tween 40, tween 60, tween 65, tween 80 and tween 85.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo butylphthalide, phospholipid, poloxamer, polyoxyethylene sorbitan fatty acid ester and water for injection, wherein the weight percentage of each component is calculated by 100 mL:
preferably, the weight percentage of each component is as follows:
the phospholipid is selected from one or more of egg yolk lecithin, soybean lecithin, PC (phosphatidylcholine), EPG (egg phosphatidyl glycerol), SPG (soybean phosphatidyl glycerol), DOPC (dioleoyl phosphatidylcholine), DOPG (dioleoyl phosphatidyl glycerol), DPPC (dipalmitoyl phosphatidylcholine), DPPG (dipalmitoyl phosphatidyl glycerol), DMPC (dimyristoyl phosphatidylcholine), DMPG (dimyristoyl phosphatidyl glycerol), DLPC (dilauroyl phosphatidylcholine), DLPG (dilauroyl phosphatidyl glycerol), preferably egg yolk lecithin and soybean lecithin; the Poloxamer is selected from one or more of Poloxamer 122, Poloxamer188, Poloxamer 237, Poloxamer 338 and Poloxamer 407; the polyoxyethylene sorbitan fatty acid ester is selected from: one or more of tween 20, tween 40, tween 60, tween 65, tween 80 and tween 85.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo-butylphthalide, phospholipid, poloxamer, polyethylene glycol surfactant and water for injection, wherein the weight percentage of each component is calculated by 100 mL:
preferably, the weight percentage of each component is as follows:
the phospholipid is selected from one or more of egg yolk lecithin, soybean lecithin, PC (phosphatidylcholine), EPG (egg phosphatidyl glycerol), SPG (soybean phosphatidyl glycerol), DOPC (dioleoyl phosphatidylcholine), DOPG (dioleoyl phosphatidyl glycerol), DPPC (dipalmitoyl phosphatidylcholine), DPPG (dipalmitoyl phosphatidyl glycerol), DMPC (dimyristoyl phosphatidylcholine), DMPG (dimyristoyl phosphatidyl glycerol), DLPC (dilauroyl phosphatidylcholine), DLPG (dilauroyl phosphatidyl glycerol), preferably egg yolk lecithin and soybean lecithin; the Poloxamer is selected from one or more of Poloxamer 122, Poloxamer188, Poloxamer 237, Poloxamer 338 and Poloxamer 407; the polyethylene glycol surfactant is selected from: one or more of polyethylene glycol-12-hydroxystearate, polyethylene glycol-VE carbonate, PEG-THS (polyethylene glycol-VE succinate), PEG-DSPE (polyethylene glycol-distearoylphosphatidylethanolamine), PEG-CHS (polyethylene glycol-cholesterol succinate), PEG-CHM (polyethylene glycol-cholesterol methyl ester), and polyethylene glycol-cholesterol sulfate.
In another embodiment of the present invention, the butylphthalide injection comprises: comprises butylphthalide or levo butylphthalide, phospholipid, poloxamer, polyethylene glycol surfactant, polyoxyethylene sorbitan fatty acid ester and water for injection, wherein the weight percentage of each component is calculated by 100 mL:
preferably, the weight percentage of each component is as follows:
the phospholipid is selected from one or more of egg yolk lecithin, soybean lecithin, PC (phosphatidylcholine), EPG (egg phosphatidyl glycerol), SPG (soybean phosphatidyl glycerol), DOPC (dioleoyl phosphatidylcholine), DOPG (dioleoyl phosphatidyl glycerol), DPPC (dipalmitoyl phosphatidylcholine), DPPG (dipalmitoyl phosphatidyl glycerol), DMPC (dimyristoyl phosphatidylcholine), DMPG (dimyristoyl phosphatidyl glycerol), DLPC (dilauroyl phosphatidylcholine), DLPG (dilauroyl phosphatidyl glycerol), preferably egg yolk lecithin and soybean lecithin; the Poloxamer is selected from one or more of Poloxamer 122, Poloxamer188, Poloxamer 237, Poloxamer 338 and Poloxamer 407; the polyethylene glycol surfactant is selected from: one or more of polyethylene glycol-12-hydroxystearate, polyethylene glycol-VE carbonate, PEG-THS (polyethylene glycol-VE succinate), PEG-DSPE (polyethylene glycol-distearoylphosphatidylethanolamine), PEG-CHS (polyethylene glycol-cholesterol succinate), PEG-CHM (polyethylene glycol-cholesterol methyl ester), and polyethylene glycol-cholesterol sulfate; the polyoxyethylene sorbitan fatty acid ester is selected from: one or more of tween 20, tween 40, tween 60, tween 65, tween 80 and tween 85.
The invention also provides a preparation method of the butylphthalide injection, which comprises the following steps:
firstly, weighing a surfactant with a prescription amount, and dissolving the surfactant in injection water;
adding butylphthalide or derivatives thereof into the solution obtained in the step I, and fully mixing to obtain clear solution;
(iii) optionally, adding a stabilizer and a pH regulator in a prescribed amount into the solution obtained in the step (ii);
fourthly, adding active carbon into the solution obtained in the second step or the third step, stirring, filtering to remove the carbon and bacteria,
fifthly, optionally, directly packaging and sterilizing the solution obtained in the step (iv), or adding a freeze-drying protective agent, packaging and freeze-drying to obtain the butylphthalide injection.
Wherein:
firstly, controlling the temperature of a solution to be 20-60 ℃; controlling the temperature of the solution to be 20-30 ℃;
and fourthly, the percentage content of the activated carbon is 0.1-0.5%.
The butylphthalide injection has the advantages that: the prepared preparation can effectively cover the special fragrance of butylphthalide; ② the prepared preparation has stable quality; the content of the butylphthalide is high, and the butylphthalide can be subpackaged into a small-volume preparation which can be used for intravenous injection and intramuscular injection, so that the clinical administration requirement is met; fourthly, the preparation process is simple, the operability is strong, and the industrialization is facilitated.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1 butylphthalide injection (water injection): comprises butylphthalide, soybean lecithin and water for injection, and the dosage of the three prescriptions is shown in the following table:
in 100 mL:
| name of material | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.25g | 0.25 |
| Soybean lecithin | 4g | 4 |
| Injection water | Adding water to 100ml |
The preparation process comprises the following steps: dissolving soybean lecithin in about 90ml of injection water at 40-60 ℃, slowly dropwise adding butylphthalide, fully stirring, crushing by using a high-pressure homogenizer, controlling the particle size to be less than 50 nanometers to obtain clear liquid, replenishing water to 100ml, adding 0.1% of activated carbon, stirring for 30 minutes, filtering to remove the carbon, sterilizing, subpackaging, 10ml each, and sterilizing.
Example 2 butylphthalide injection (water injection): comprises butylphthalide, polyethylene glycol-12 hydroxystearate and water for injection, and the dosage of the three prescriptions is shown in the following table:
| name of material | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.25g | 0.25 |
| Polyethylene glycol-12 Hydroxystearate | 1g | 1 |
| Injection water | Adding water to 100ml |
The preparation process comprises the following steps: dissolving polyethylene glycol-12-hydroxystearate in about 90ml of injection water at the temperature of 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drop appears on the liquid surface to obtain clear liquid, replenishing water to 100ml, adding 0.2% activated carbon, stirring for 30 minutes, filtering to remove carbon, sterilizing, subpackaging, and sterilizing 10ml per bottle.
Example 3 butylphthalide injection (lyophilized powder): comprises butylphthalide, polyethylene glycol-12 hydroxystearate and water for injection, and the dosage of the three prescriptions is shown in the following table:
| name of material | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.5g | 0.5 |
| Polyethylene glycol-12 Hydroxystearate | 2g | 2 |
| Mannitol | 6g | 6 |
| Glucose | 1.5g | 1.5 |
| Injection water | Adding water to 100ml |
The preparation process comprises the following steps: dissolving polyethylene glycol-12-hydroxystearate in about 90ml of injection water at the temperature of 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drop appears on the liquid surface, adding mannitol and glucose to dissolve to obtain clear liquid, replenishing water to 100ml, adding 0.1% activated carbon, stirring for 30 minutes, filtering to remove carbon, sterilizing, subpackaging, 5ml each, and freeze-drying.
Example 4 butylphthalide injection (water injection): comprises butylphthalide, tween 80 and water for injection, and the dosage of the three prescriptions is shown in the following table:
| name of material | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.25g | 0.25 |
| Tween 80 | 2g | 2 |
| Injection water | Adding water to 100ml |
The preparation process comprises the following steps: dissolving Tween 80 in about 90ml of injection water at 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drop appears on the liquid surface to obtain clear liquid, replenishing water to 100ml, adding 0.2% activated carbon, stirring for 30 minutes, filtering to remove carbon, sterilizing, subpackaging with 10ml of each bottle, and sterilizing.
Example 5 butylphthalide injection (water injection): comprises butylphthalide, Poloxamer188 and water for injection, and the dosage of the three ingredients is shown in the following table:
| name of material | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.25g | 0.25 |
| Poloxamer 188 | 3g | 3 |
| Injection water | Adding water to 100ml |
The preparation process comprises the following steps: at the temperature of 20-30 ℃, Poloxamer188 is dissolved in about 90ml of injection water, butylphthalide is slowly dripped, the mixture is fully stirred, no oil drop appears on the liquid surface, clear liquid is obtained, water is supplemented to 100ml, 0.2% activated carbon is added, the mixture is stirred for 30 minutes, carbon is removed by filtration, sterilization and split charging are carried out, 10ml of each product is sterilized.
Example 6 butylphthalide injection (water injection): comprises butylphthalide, polyethylene glycol-12 hydroxystearate, egg yolk lecithin and water for injection, and the dosage of the three prescriptions is shown in the following table:
| name of material | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.5g | 0.5 |
| Polyethylene glycol-12 Hydroxystearate | 3g | 3 |
| Egg yolk lecithin | 0.1g | 0.1 |
| Injection water | Adding water to 100ml |
The preparation process comprises the following steps: dissolving polyethylene glycol-12-hydroxystearate and yolk lecithin in about 90ml of injection water at 40-60 ℃, cooling to 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drops appear on the liquid surface to obtain a clear liquid, replenishing water to 100ml, adding 0.1% activated carbon, stirring for 30 minutes, filtering to remove carbon, sterilizing, subpackaging with 5ml each, and sterilizing.
Example 7 butylphthalide injection (water injection): comprises butylphthalide, polyethylene glycol-12 hydroxystearate, tween 80 and water for injection, and the dosage of the prescription is shown in the following table:
| name of material | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.5g | 0.5 |
| Polyethylene glycol-12 Hydroxystearate | 2.4g | 2.4 |
| Tween 80 | 0.1g | 0.1 |
| Injection water | Adding water to 100ml |
The preparation process comprises the following steps: dissolving polyethylene glycol-12-hydroxystearate and tween 80 in about 90ml of injection water at 40-60 ℃, cooling to 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drop appears on the liquid surface to obtain a clear liquid, replenishing water to 100ml, adding 0.1% activated carbon, stirring for 30 minutes, filtering to remove carbon, sterilizing, subpackaging with 5ml each, and sterilizing.
Example 8 butylphthalide injection (water injection): comprises butylphthalide, Tween 80, egg yolk lecithin and water for injection, and the dosage of the prescription is shown in the following table:
| name of material | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.25g | 0.25 |
| Tween 80 | 1.8g | 1.8 |
| Egg yolk lecithin | 0.5g | 0.5 |
| Injection water | Adding water to 100ml |
The preparation process comprises the following steps: dissolving Tween 80 and egg yolk lecithin in about 90ml of injection water at the temperature of 30-60 ℃, cooling to 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drops appear on the liquid surface to obtain clear liquid, replenishing water to 100ml, adding 0.5% activated carbon, stirring for 30 minutes, filtering to remove the carbon, sterilizing, subpackaging, 10ml each, and sterilizing.
Example 9 butylphthalide injection (water injection): comprises butylphthalide, yolk lecithin, Poloxamer188 and water for injection, and the weight percentage of each component is as follows based on 100 mL:
| components | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.25g | 0.25 |
| Egg yolk lecithin | 0.1g | 0.1 |
| Poloxamer 188 | 2.6g | 2.6 |
| Water for injection | Adding water to 100ml |
The preparation process comprises the following steps: at the temperature of 30-60 ℃, dissolving Poloxamer188 and egg yolk lecithin in about 90ml of injection water, cooling to 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drop appears on the liquid surface to obtain clear liquid, replenishing water to 100ml, adding 0.5% activated carbon, stirring for 30 minutes, filtering to remove carbon, sterilizing, subpackaging 10ml each, and sterilizing.
Example 10 butylphthalide injection (water injection): comprises butylphthalide, polyethylene glycol-12 hydroxystearate, Poloxamer188 and water for injection, and the weight percentage of each component is as follows based on 100 mL:
| components | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.25g | 0.25 |
| Polyethylene glycol-12 Hydroxystearate | 1g | 1 |
| Poloxamer 188 | 1g | 1 |
| Water for injection | Adding water to 100ml |
The preparation process comprises the following steps: dissolving polyethylene glycol-12-hydroxystearate and Poloxamer188 in about 90ml of injection water at 30-60 ℃, cooling to 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drops appear on the liquid surface to obtain a clear liquid, replenishing water to 100ml, adding 0.5% activated carbon, stirring for 30 minutes, filtering to remove carbon, sterilizing, subpackaging, 10ml each, and sterilizing.
Example 11 butylphthalide injection (water injection): comprises butylphthalide, Tween 80, Poloxamer188 and water for injection, and the weight percentage of each component is as follows based on 100 mL:
| components | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.25g | 0.25 |
| Tween 80 | 1g | 1 |
| Poloxamer 188 | 2g | 2 |
| Water for injection | Adding water to 100ml |
The preparation process comprises the following steps: dissolving Tween 80 and Poloxamer188 in about 90ml of injection water at 30-60 ℃, cooling to 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drops appear on the liquid surface to obtain a clear liquid, replenishing water to 100ml, adding 0.5% activated carbon, stirring for 30 minutes, filtering to remove carbon, sterilizing, subpackaging 10ml each, and sterilizing.
Example 12 butylphthalide injection (water injection): comprises butylphthalide, Poloxamer188, egg yolk lecithin, Tween 80 and water for injection, and the dosage of the prescription is shown in the following table:
| name of material | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.25g | 0.25 |
| Poloxamer 188 | 1.0g | 1.0 |
| Tween 80 | 1.5g | 1.5 |
| Egg yolk lecithin | 0.1g | 0.1 |
| Injection water | Adding water to 100ml |
The preparation process comprises the following steps: at the temperature of 30-60 ℃, dissolving Poloxamer188, Tween 80 and egg yolk lecithin in about 90ml of injection water, cooling to 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drops appear on the liquid surface to obtain a clear liquid, replenishing water to 100ml, adding 0.5% activated carbon, stirring for 30 minutes, filtering to remove the carbon, sterilizing, subpackaging, and sterilizing, wherein 10ml of each bottle is sterilized.
Example 13 butylphthalide injection (water injection): comprises butylphthalide, polyethylene glycol-12 hydroxystearate, tween 80, Poloxamer188 and water for injection, and the prescription dosage is shown in the following table:
| name of material | Amount of prescription | The weight percentage is% |
| Butylphthalide | 0.25g | 0.25 |
| Polyethylene glycol-12 Hydroxystearate | 1g | 1 |
| Tween 80 | 0.4g | 0.4 |
| Poloxamer 188 | 0.2g | 0.2 |
| Injection water | Adding water to 100ml |
The preparation process comprises the following steps: dissolving polyethylene glycol-12 hydroxystearate, tween 80 and Poloxamer188 in about 90ml of injection water at 30-60 ℃, cooling to 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drop appears on the liquid surface to obtain a clear liquid, supplementing water to 100ml, adding 0.5% activated carbon, stirring for 30 minutes, filtering to remove carbon, sterilizing, subpackaging, 10ml each, and sterilizing.
Example 14 butylphthalide injection (water injection): comprises butylphthalide, polyethylene glycol-12 hydroxystearate, egg yolk lecithin, tween 80 and water for injection, and the dosage of the prescription is shown in the following table:
| name of material | Amount of prescription | The weight percentage is% |
| Butylphthalide | 1.25g | 1.25 |
| Polyethylene glycol-12 Hydroxystearate | 4g | 4 |
| Egg yolk lecithin | 0.1g | 0.1 |
| Tween 80 | 1.2g | 1.2 |
| Injection water | Adding water to 100ml |
The preparation process comprises the following steps: dissolving polyethylene glycol-12-hydroxystearate, egg yolk lecithin and tween 80 in about 90ml of injection water at 40-60 ℃, cooling to 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drop appears on the liquid surface to obtain clear liquid, replenishing water to 100ml, adding 0.5% activated carbon, stirring for 30 minutes, filtering to remove the carbon, sterilizing, subpackaging, 2ml each, and sterilizing.
Example 15 butylphthalide injection (water injection): comprises butylphthalide, polyethylene glycol-12 hydroxystearate, egg yolk lecithin, tween 80, Poloxamer188 and water for injection, and the dosage of the prescription is shown in the following table:
the preparation process comprises the following steps: dissolving polyethylene glycol-12 hydroxystearate, yolk lecithin, tween 80 and Poloxamer188 in about 90ml of injection water at 40-60 ℃, cooling to 20-30 ℃, slowly dropwise adding butylphthalide, fully stirring until no oil drop appears on the liquid surface to obtain a clear liquid, replenishing water to 100ml, adding 0.5% activated carbon, stirring for 30 minutes, filtering to remove carbon, sterilizing, subpackaging, 2ml each, and sterilizing.
EXAMPLE 16 sample stability test
The samples prepared in examples 1-15 were left to stand (40 ℃, RH 75%) and tested for stability tests, and the results were as follows:
the result shows that the butylphthalide injection of the invention has stable quality after being stored for 2 years.
EXAMPLE 17 compatibility stability test of samples
For the samples prepared in examples 1 to 15, 100ml of 0.9% sodium chloride injection and 100ml of 5% glucose injection are used as diluted solutions respectively, and the diluted solutions are left at 40 ℃ to examine the stability under clinical use conditions:
the result shows that the butylphthalide injection is stable within 8 hours under the clinical use condition and meets the clinical medication requirement.
Example 18 vascular irritation test
1. Experiment design:
the samples prepared in examples 1-15 were administered by intravenous injection to rabbit ears at 5mL dose.
2. Method of administration
30 healthy New Zealand rabbits were selected, and the test drugs were injected intravenously into the left ear margin of the rabbit and the same volume of sodium chloride injection was injected intravenously into the right ear margin of the rabbit as a control. After 30 rabbits were sequentially administered with the test drugs, 5mL of 0.9% sodium chloride injection was administered, 1 time a day, for 3 consecutive days. Pre-dose and 48 hours and 14 days after the last dose were weighed 1 time each.
3. General observations and animal draw
The reaction between the animal and the blood vessel injection part is observed and recorded before the administration every day, 1 animal of the tested medicine is killed by bleeding respectively 48 hours after the last administration, after the reaction of the blood vessel tissue is observed and recorded by naked eyes, double rabbit ears are reduced from the ear root (the left ear is reduced firstly, the right ear is cut afterwards and marked), then a section of rabbit ear specimen is cut and fixed in 10% neutral formaldehyde solution respectively (the specimen is about 8cm long and about 1cm wide, the far-end incision is about 0.5cm away from the first needle eye, the near-end incision is about 2cm away from the third needle eye, and the thread hanging end is the near-end). Each of the 1 animals that left the test drug was observed for a further 14 days after the last administration and subjected to pathological examination.
Cutting a section at the far end by taking the first needle eye as a boundary; cutting two sections at the proximal end by taking the third needle eye as a boundary; and (3) transversely cutting blood vessels during sectioning, sectioning with conventional paraffin, wherein the sectioning thickness is about 4-5 mu m, and then carrying out pathological histological examination.
4. Determination of results
And carrying out comprehensive judgment according to the results of visual observation and pathological examination. The reaction at the injection site of the blood vessel of the animal was visually observed and recorded before the administration every day, and the blood vessel surface of the needle insertion site of the rabbit ear at the administration side and the control side of the animal, in which the test drug was visually observed, was red in color and the area was from 0.1cm × 0.2cm to 0.2cm × 1.0cm during the administration. At 48 hours after the last administration, the blood vessels of the bilateral rabbit ears of 2 rabbits of the tested drug have clear outlines, and the thickness of the rabbit ears is uniform and is not obviously changed. The blood vessels of the ears of the 15 rabbits dissected for the tested medicine 14 days after the last administration are clear in outline, and the ears of the rabbits are uniform in thickness and have no obvious change.
The 15 rabbits of the tested drug are subjected to autopsy 48 hours after the last administration, and 6 rabbits of the rest tested drug are subjected to autopsy after the 2-week recovery period, and no remarkable irritation reaction such as degeneration or necrosis of vascular tissues is seen in the pathological histological examination.
Example 19 muscle stimulation experiments
1. Experiment design:
the samples prepared in examples 1 to 15 were administered by intramuscular injection to the quadriceps femoris of rabbits in an amount of 1 mL.
2. Method of administration and Experimental observations
2 healthy New Zealand rabbits were taken for each sample, and the test drug was injected intramuscularly in the left quadriceps of the rabbits and the equal volume of sodium chloride injection was injected intramuscularly in the right quadriceps of the rabbits by aseptic technique. It is administered 1 time daily for 3 days. The animal and injection site reactions were observed and recorded prior to each dose. At 48 hours after the last administration, 1 animal each of the test drugs was taken, sacrificed by exsanguination, the quadriceps femoris muscle was exposed by dissection, longitudinally cut, visually observed and recorded for the stimulation response at the injection site, and then the muscle at the injection site was examined pathologically and histologically. Each of the 1 animals with the test drug remained on observation for 14 days after the last administration, and was examined for injection site pathology.
3. Determination of results
No obvious change is observed at 48 hours and 14 days after the last administration, and the surface and deep muscle tissues of the injection site have high elasticity and luster.
Pathological observation 48 hours and 14 days after the last administration revealed that the muscle tissue structures were normal and the muscle fibers were well-aligned on the administration side and the control side.
The results of visual observation and pathological observation show that the butylphthalide injection sample of the invention has no obvious irritative changes such as degeneration, necrosis and the like on the injection part of a New Zealand rabbit.
In conclusion, the butylphthalide injection disclosed by the invention is small in volume, simple and easy to operate in preparation process, stable in quality, free of irritation to blood vessels and muscles, high in safety and capable of meeting the clinical medication requirements.
Claims (19)
1. The butylphthalide injection is prepared from butylphthalide, a surfactant and water for injection, wherein the weight ratio of the butylphthalide to the surfactant to the water for injection is 1: 3-20: 383-400, the surfactant is selected from one or more of phospholipid, Tween 80 and Poloxamer188, and the phospholipid is selected from egg yolk lecithin and soybean lecithin.
2. The butylphthalide injection according to claim 1, wherein: the butylphthalide is racemic butylphthalide or levo-butylphthalide.
3. The butylphthalide injection according to claim 1, wherein: the butylphthalide injection also comprises a stabilizer and a pH regulator.
4. The butylphthalide injection according to claim 3, wherein: the stabilizer is selected from one or more of inert gas and antioxidant.
5. The butylphthalide injection according to claim 4, wherein: the stabilizer is selected from one or more of nitrogen, tocopherol, vitamin C or EDTA-2 Na.
6. The butylphthalide injection according to claim 3, wherein: the pH adjusting agent comprises an organic acid base, an inorganic acid base or a combination thereof.
7. The butylphthalide injection according to claim 6, wherein: the organic acid is selected from one or more of citric acid, lactic acid, fumaric acid, tartaric acid, acetic acid, gluconic acid, lactobionic acid, sorbic acid, succinic acid, maleic acid, oxalic acid, formic acid, acetic acid, benzenesulfonic acid, benzoic acid, glutamic acid, lysine and aspartic acid; the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and hydrobromic acid.
8. The butylphthalide injection according to claim 3, wherein: the pH regulator comprises one or more of potassium dihydrogen phosphate and sodium dihydrogen phosphate.
9. The butylphthalide freeze-dried powder injection preparation prepared from the butylphthalide injection of claim 1.
10. The butylphthalide lyophilized powder injection preparation according to claim 9, wherein: also comprises a freeze-drying protective agent.
11. The butylphthalide lyophilized powder injection preparation according to claim 10, wherein: the freeze-drying protective agent is selected from one or combination of more of maltose, mannitol and glucose.
12. The butylphthalide injection according to claim 1, wherein: the weight percentage of each component is as follows:
。
13. The butylphthalide injection according to claim 1, wherein: the weight percentage of each component is as follows:
。
14. The butylphthalide injection according to claim 1, wherein: the weight percentage of each component is as follows:
。
15. The butylphthalide injection according to claim 1, wherein: the weight percentage of each component is as follows:
。
16. The butylphthalide injection according to claim 1, wherein: the weight percentage of each component is as follows:
。
17. The butylphthalide injection according to claim 1, wherein: the weight percentage of each component is as follows:
。
18. The butylphthalide injection according to claim 1, wherein: the weight percentage of each component is as follows:
。
19. A method for preparing the butylphthalide injection according to claim 1, comprising the following steps:
firstly, weighing a surfactant with a prescription amount, and dissolving the surfactant in injection water;
adding butylphthalide into the solution obtained in the step one, and fully mixing to obtain a clear solution;
adding active carbon into the solution obtained in the second step, stirring, filtering to remove carbon and bacteria;
fourthly, directly subpackaging and sterilizing the solution obtained in the third step to obtain the butylphthalide injection.
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| CN105030760B (en) * | 2014-04-24 | 2018-10-02 | 长弘生物科技股份有限公司 | Stable pharmaceutical composition |
| CN105688220A (en) * | 2014-12-15 | 2016-06-22 | 四川曼赛思医药科技有限公司 | Pharmaceutical composition containing butylphthalide and novel solubilizer |
| CN110548004B (en) * | 2018-05-30 | 2023-05-16 | 成都施贝康生物医药科技有限公司 | Stable butylphthalide high-capacity injection and preparation method thereof |
| CN111346089A (en) * | 2018-12-22 | 2020-06-30 | 江苏先声药业有限公司 | Medicinal preparation and preparation method thereof |
| KR20220156597A (en) * | 2020-03-20 | 2022-11-25 | 씨에스피씨 엔비피 파머슈티컬 캄파니 리미티드 | Uses of Butylphthalide and Its Derivatives |
| CN111544398A (en) * | 2020-06-24 | 2020-08-18 | 李书剑 | Argatroban freeze-dried powder and preparation method thereof |
| CN111603446A (en) * | 2020-07-13 | 2020-09-01 | 广东隆赋药业股份有限公司 | Butylphthalide-containing nasal spray, and preparation method and application thereof |
| CN114681389A (en) * | 2020-12-29 | 2022-07-01 | 中国科学院上海药物研究所 | Butylphthalide composition delivered through oral mucosa and application thereof |
| CN115844815A (en) * | 2021-09-27 | 2023-03-28 | 河北菲尼斯生物技术有限公司 | Butylphthalide sterilization injection and preparation method and application thereof |
| CN114886848B (en) * | 2022-05-20 | 2024-03-08 | 山东泰合医药科技有限公司 | Preparation method of nano micelle composition and prepared nano micelle composition |
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| CN1615938A (en) * | 2004-09-20 | 2005-05-18 | 周桂荣 | Medicine for treating acute ischemic cerebral apoplexy and its preparing method |
| CN1839824A (en) * | 2006-01-18 | 2006-10-04 | 高春平 | Emulsion medicine containing n-NBP for injection and its preparation method |
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| CN100367951C (en) * | 2005-12-16 | 2008-02-13 | 石药集团恩必普药业有限公司 | Butyl benzene phthalein vein emulsion and its application |
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| CN1839824A (en) * | 2006-01-18 | 2006-10-04 | 高春平 | Emulsion medicine containing n-NBP for injection and its preparation method |
| CN103505409B (en) * | 2012-06-27 | 2017-12-26 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of 3-n-butylphthalide injection and preparation method thereof |
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