CN103505409B - A kind of 3-n-butylphthalide injection and preparation method thereof - Google Patents
A kind of 3-n-butylphthalide injection and preparation method thereof Download PDFInfo
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- CN103505409B CN103505409B CN201210214131.0A CN201210214131A CN103505409B CN 103505409 B CN103505409 B CN 103505409B CN 201210214131 A CN201210214131 A CN 201210214131A CN 103505409 B CN103505409 B CN 103505409B
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Abstract
The present invention relates to a kind of 3-n-butylphthalide injection and preparation method thereof.The 3-n-butylphthalide injection of the present invention, comprising butylphenyl phthaleine or derivatives thereof, surfactant and water for injection, one or more of the surfactant in phosphatide, the hydroxy stearic acid ester of polyethylene glycol 12, polyethylene glycol VE carbonic esters, polyethylene glycol VE succinates, polyethylene glycol DSPE, polyethylene glycol cholesterol succinate, polyethylene glycol cholesterol methyl esters, polyethylene glycol cholesterol sulfate, polyoxyethylene sorbitan fatty acid ester class, poloxamer.The 3-n-butylphthalide injection of the present invention can effectively cover the peat-reek of butylphenyl phthaleine；Steady quality；Butylphthalide content is high, can be distributed into the preparation of small size, can be not only used for intravenous injection and can be used for intramuscular injection, meets clinical administration demand；Preparation technology is simple, strong operability, beneficial to industrialization.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of medicaments injection and preparation method thereof, in particular to a kind of fourth
Phthalide parenteral solution and preparation method thereof.
Background technology
Butylphenyl phthaleine（3-n-butylphthalide, abbreviation NBP）, complete (the H)-isobenzofuranone of name 3- butyl -1, also known as
Butylphthalide, it is the raceme extracted from celery seed, also can be artificial synthesized.Butylphenyl phthaleine is a kind of oily liquids, insoluble
Yu Shui, there is strong celery taste, an asymmetric carbon atom is contained in molecule, therefore two kinds of optical isomers be present in it, i.e., it is left
Revolve butylphenyl phthaleine and d-3-n-butylphthalide.The infarct that butylphenyl phthaleine can be reduced after focal cerebral ischemia, increase ischemic region cerebral blood flow (CBF) and
Improve Cerebral Region microcirculation, protect mitochondrial function, mitigate the degree of nervous function damage, improve the energy of global cerebral ischemia hindbrain
Amount metabolism etc., act on multiple links of cerebral ischemia pathology.Chinese patent 98125618.X, 03137457.3,
200310100222.2 and 200410001748.X discloses butylphenyl phthaleine in antithrombus formation and platelet aggregation-against, left-handed respectively
Application of the butylphenyl phthaleine in prevention and treatment dementia, cerebral infarction and brain ischemia medicament.
At present, butylphenyl phthaleine commercialized product has soft capsule and infusion solution.Soft capsule is oral formulations, although the formulation can
The peat-reek of medicine is covered, but can not reach and quickly release the drug, be rapidly reached the purpose of therapeutic effect.Infusion solution uses cyclodextrin
Inclusion technique, although solving the problems, such as that soft capsule can not quickly release the drug, because volume is big, can only be injected intravenously or
Instil, be not well positioned to meet clinical application demand still.
Chinese patent 200410012533.8 discloses a kind of butylphenyl phthaleine freeze drying powder injection, by butylphenyl phthaleine, emulsifying agent and helps
Emulsifying agent, excipient and water for injection composition.Chinese patent 200510102355.2 discloses a kind of butyl benzene phthalein vein emulsion, by
Butylphenyl phthaleine, oil, emulsifying agent, isotonic agent, water for injection composition, carry out emulsification with two step emulsion dispersion methods and be made.Two kinds of formulations
The solubility of butylphenyl phthaleine is added, while adds the targeting of butylphenyl phthaleine brain tissue, reduces its toxic side effect.But it is prepared
Technique is complex, and belongs to non-thermostable system, it may occur that demulsifying phenomenon, influences product quality；In addition, the formulation
Still for intravenous injection or instil.
Chinese patent application 200610081440.X discloses a kind of butylphenyl phthaleine concentrated solution, containing butylphenyl phthaleine, and at least contains
There is a kind of pharmaceutically acceptable carrier, carrier includes：Nonaqueous solvents, solubilizer, cosolvent, antioxidant and stabilizer.Should
Formulation need to be with glucose injection or sodium chloride injection progress compatibility when using, more difficult operation when clinical practice dilutes, and
Still for intravenous injection or instil.
To sum up, butylphenyl phthaleine formulation complex process disclosed in prior art, quality is unstable, and is not well positioned to meet still and faces
Bed medication demand.
The content of the invention
In view of the problem of prior art is present, present invention is primarily aimed at providing, a kind of small volume, preparation technology are simple,
Butylphenyl phthaleine injection of intramuscular injection and intravenous injection and preparation method thereof can be used for simultaneously.
Therefore, one aspect of the present invention provides a kind of 3-n-butylphthalide injection, includes butylphenyl phthaleine or derivatives thereof, surfactant
And water for injection.
Wherein：The butylphenyl phthaleine is dl-3-n-butylphthalide or levo butyl phthalide.
The weight ratio of butylphenyl phthaleine or derivatives thereof, surfactant and water for injection is：1:2~50:50 ~ 500, be preferably：
1:3~20:80~400。
The surfactant is selected from：Phosphatide, HS15（Solutol® HS 15）, it is poly-
Ethylene glycol-VE carbonic esters, PEG-THS（Polyethylene glycol-VE succinates）、PEG-DSPE（Polyethylene glycol-distearoylphosphatidyl
Monoethanolamine）、PEG-CHS（PEG-CHOL succinate）、PEG-CHM（PEG-CHM）, poly- second two
Alcohol-cholesterol sulfate, polyoxyethylene sorbitan fatty acid ester class（Tween type：Tween）, poloxamer.Further,
The phosphatide includes separate sources, the egg yolk lecithin of different purity, soybean lecithin, PC（Phosphatidyl choline）、EPG（Lecithin
Phosphatidyl glycerol）、SPG（Soy phosphatidylglycerol）、DOPC（DOPC）、DOPG（DOPG）、
DPPC（DPPC）、DPPG（DPPG）、DMPC（Dimyristoyl phosphatidyl choline）、
DMPG（GLYCEROL,DIMYRISTOYL PHOSPHATIDYL）、DLPC（DLPC）、DLPG（PE）；
The HS15, TPGS, polyethylene glycol-VE carbonic esters, polyethylene glycol-VE
Succinate, PEG2000-DSPE, PEG-CHOL succinate, polyethylene glycol-courage are solid
Alcohol methyl esters, PEG-CHOL sulfuric ester（Hereinafter referred polyethylene glycols surfactant）In polyethylene glycol molecule
Measure as 300 ~ 30000；Polyoxyethylene sorbitan fatty acid ester class is polysorbas20, polysorbate40, polysorbate60, polysorbate65, tween
80th, polysorbate85；The poloxamer is selected from Poloxamer 122, Poloxamer 188, Poloxamer 237, Poloxamer
338、Poloxamer 407。
HS15, PEG-THS, PEG-CHS, PEG-CHM structural formula are as follows：
HS15
PEG-THS
PEG-CHS
PEG-CHM
n=5~500（PEG molecular weight is 300 ~ 30000）.
Optionally, the 3-n-butylphthalide injection also stabilizer comprising other compositions, pH adjusting agent etc..The stabilizer bag
Include nitrogen, inert gas, antioxidant, tocopherol, vitamin C or EDTA-2Na；The pH adjusting agent include organic acids and base and
Inorganic acid alkali, organic acid are selected from citric acid, lactic acid, fumaric acid, tartaric acid, gluconic acid, lactobionic acid, sorbic acid, butanedioic acid, horse
The one or more come in sour, oxalic acid, formic acid, acetic acid, benzene sulfonic acid, benzoic acid, glutamic acid, lysine, aspartic acid etc.；Nothing
One or more of the machine acid in hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate etc.；It is organic
Alkali is selected from ammoniacal liquor, pyridine, diethylamine, triethylamine, EDTA, sodium methoxide, potassium ethoxide, potassium tert-butoxide, butyl lithium, phenyl lithium, two different
Propyl group amido lithium（LDA）, hexamethyldisilazane lithium（LiHMDS）One or more in, inorganic base be selected from sodium hydroxide,
Potassium hydroxide, sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, potassium phosphate
One or more in.
The 3-n-butylphthalide injection of the present invention can exist in the form of liquid drugs injection, freeze drying technology can also be used to obtain solid system
Agent.One or more of combinations that conventional freeze drying protectant includes but is not limited in maltose, mannitol, glucose, it is such as sweet
Dew alcohol 6% is combined with glucose 1.5%, mannitol 6% is combined with glucose 3%, mannitol 6% is combined with maltose 1.5%, mannitol
2% is combined etc. with glucose 4% and maltose 8%.
In one embodiment of the invention, 3-n-butylphthalide injection composition is：Include butylphenyl phthaleine or levo butyl phthalide, phosphorus
Fat and water for injection, in terms of 100mL, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Phosphatide | 0.04~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Phosphatide | 0.4~6.0 |
| Water for injection | Surplus |
The phosphatide is selected from egg yolk lecithin, soybean lecithin, PC（Phosphatidyl choline）、EPG（EPG）、
SPG（Soy phosphatidylglycerol）、DOPC（DOPC）、DOPG（DOPG）、DPPC（Two palms
Phosphatidyl choline）、DPPG（DPPG）、DMPC（Dimyristoyl phosphatidyl choline）、DMPG（Two Pork and beans
Cool acyl phosphatidyl glycerol）、DLPC（DLPC）、DLPG（PE）In one kind or more
Kind.
In another embodiment of the present invention, 3-n-butylphthalide injection composition is：Comprising butylphenyl phthaleine or levo butyl phthalide,
Polyethylene glycols surfactant and water for injection, in terms of 100mL, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Polyethylene glycols surfactant | 0.04~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Polyethylene glycols surfactant | 0.4~6.0 |
| Water for injection | Surplus |
The polyethylene glycols surfactant is selected from：HS15, polyethylene glycol-VE carbonic acid
Ester, PEG-THS（Polyethylene glycol-VE succinates）、PEG-DSPE（PEG2000-DSPE）、PEG-
CHS（PEG-CHOL succinate）、PEG-CHM（PEG-CHM）, PEG-CHOL sulfuric acid
One or more in ester, preferably HS15 or itself and other polyethylene glycols surfactants
Combination.
In another embodiment of the present invention, 3-n-butylphthalide injection composition is：Comprising butylphenyl phthaleine or levo butyl phthalide,
Polyoxyethylene sorbitan fatty acid ester class and water for injection, in terms of 100mL, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.04~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.4~6.0 |
| Water for injection | Surplus |
The polyoxyethylene sorbitan fatty acid ester class is selected from：Polysorbas20, polysorbate40, polysorbate60, polysorbate65, tween
80th, one kind in polysorbate85 or its any combination, preferably Tween 80 or itself and other polyoxylene sorbitan fatties acid
The combination of esters.
In another embodiment of the present invention, 3-n-butylphthalide injection composition is：Comprising butylphenyl phthaleine or levo butyl phthalide,
Poloxamer and water for injection, in terms of 100mL, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Poloxamer | 0.04~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Poloxamer | 1.0~6.0 |
| Water for injection | Surplus |
The poloxamer is selected from Poloxamer 122, Poloxamer 188, Poloxamer 237, Poloxamer
338th, one kind in Poloxamer 407 or its any combination.
In another embodiment of the present invention, 3-n-butylphthalide injection composition is：Comprising butylphenyl phthaleine or levo butyl phthalide,
Phosphatide, polyethylene glycols surfactant and water for injection, in terms of 100mL, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Polyethylene glycols surfactant | 0.04~10.0 |
| Phosphatide | 0.01~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Polyethylene glycols surfactant | 0.4~6.0 |
| Phosphatide | 0.05~6.0 |
| Water for injection | Surplus |
The phosphatide is selected from egg yolk lecithin, soybean lecithin, PC（Phosphatidyl choline）、EPG（EPG）、
SPG（Soy phosphatidylglycerol）、DOPC（DOPC）、DOPG（DOPG）、DPPC（Two palms
Phosphatidyl choline）、DPPG（DPPG）、DMPC（Dimyristoyl phosphatidyl choline）、DMPG（Two Pork and beans
Cool acyl phosphatidyl glycerol）、DLPC（DLPC）、DLPG（PE）In one kind or more
Kind；The polyethylene glycols surfactant is selected from：HS15, polyethylene glycol-VE carbonic esters,
PEG-THS（Polyethylene glycol-VE succinates）、PEG-DSPE（PEG2000-DSPE）、PEG-CHS
（PEG-CHOL succinate）、PEG-CHM（PEG-CHM）, PEG-CHOL sulfuric ester
In one or more.
In another embodiment of the present invention, 3-n-butylphthalide injection composition is：Comprising butylphenyl phthaleine or levo butyl phthalide,
Polyethylene glycols surfactant, polyoxyethylene sorbitan fatty acid ester class and water for injection, in terms of 100mL, each component
Percentage by weight be：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Polyethylene glycols surfactant | 0.04~10.0 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.02~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Polyethylene glycols surfactant | 0.4~6.0 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.1~6.0 |
| Water for injection | Surplus |
The polyethylene glycols surfactant is selected from：HS15, polyethylene glycol-VE carbonic acid
Ester, PEG-THS（Polyethylene glycol-VE succinates）、PEG-DSPE（PEG2000-DSPE）、PEG-
CHS（PEG-CHOL succinate）、PEG-CHM（PEG-CHM）, PEG-CHOL sulfuric acid
One or more in ester；The polyoxyethylene sorbitan fatty acid ester class is selected from：Polysorbas20, polysorbate40, polysorbate60, tell
One or more in temperature 65, Tween 80, polysorbate85.
In another embodiment of the present invention, 3-n-butylphthalide injection composition is：Comprising butylphenyl phthaleine or levo butyl phthalide,
Phosphatide, polyoxyethylene sorbitan fatty acid ester class and water for injection, in terms of 100mL, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Phosphatide | 0.04~10.0 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.01~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Phosphatide | 0.4~6.0 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.1~6.0 |
| Water for injection | Surplus |
The phosphatide is selected from egg yolk lecithin, soybean lecithin, PC（Phosphatidyl choline）、EPG（EPG）、
SPG（Soy phosphatidylglycerol）、DOPC（DOPC）、DOPG（DOPG）、DPPC（Two palms
Phosphatidyl choline）、DPPG（DPPG）、DMPC（Dimyristoyl phosphatidyl choline）、DMPG（Two Pork and beans
Cool acyl phosphatidyl glycerol）、DLPC（DLPC）、DLPG（PE）In one kind or more
Kind；The polyoxyethylene sorbitan fatty acid ester class is selected from：Polysorbas20, polysorbate40, polysorbate60, polysorbate65, Tween 80, tell
One or more in temperature 85.
In another embodiment of the present invention, 3-n-butylphthalide injection composition is：Comprising butylphenyl phthaleine or levo butyl phthalide,
Phosphatide, poloxamer and water for injection, in terms of 100mL, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Phosphatide | 0.01~10.0 |
| Poloxamer | 0.04~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Phosphatide | 0.1~6.0 |
| Poloxamer | 1.0~6.0 |
| Water for injection | Surplus |
The phosphatide is selected from egg yolk lecithin, soybean lecithin, PC（Phosphatidyl choline）、EPG（EPG）、
SPG（Soy phosphatidylglycerol）、DOPC（DOPC）、DOPG（DOPG）、DPPC（Two palms
Phosphatidyl choline）、DPPG（DPPG）、DMPC（Dimyristoyl phosphatidyl choline）、DMPG（Two Pork and beans
Cool acyl phosphatidyl glycerol）、DLPC（DLPC）、DLPG（PE）In one kind or more
Kind；The poloxamer be selected from Poloxamer 122, Poloxamer 188, Poloxamer 237, Poloxamer 338,
One or more in Poloxamer 407.
In another embodiment of the present invention, 3-n-butylphthalide injection composition is：Comprising butylphenyl phthaleine or levo butyl phthalide,
Polyethylene glycols surfactant, poloxamer and water for injection, in terms of 100mL, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Polyethylene glycols surfactant | 0.01~10.0 |
| Poloxamer | 0.04~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Polyethylene glycols surfactant | 0.1~6.0 |
| Poloxamer | 0.4~6.0 |
| Water for injection | Surplus |
The polyethylene glycols surfactant is selected from：HS15, polyethylene glycol-VE carbonic acid
Ester, PEG-THS（Polyethylene glycol-VE succinates）、PEG-DSPE（PEG2000-DSPE）、PEG-
CHS（PEG-CHOL succinate）、PEG-CHM（PEG-CHM）, PEG-CHOL sulfuric acid
One or more in ester；The poloxamer be selected from Poloxamer 122, Poloxamer 188, Poloxamer 237,
One or more in Poloxamer 338, Poloxamer 407.
In another embodiment of the present invention, 3-n-butylphthalide injection composition is：Comprising butylphenyl phthaleine or levo butyl phthalide,
Polyoxyethylene sorbitan fatty acid ester class, poloxamer and water for injection, in terms of 100mL, the percentage by weight of each component
For：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.01~10.0 |
| Poloxamer | 0.04~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.1~6.0 |
| Poloxamer | 0.4~6.0 |
| Water for injection | Surplus |
It is selected from the polyoxyethylene sorbitan fatty acid ester class：Polysorbas20, polysorbate40, polysorbate60, polysorbate65, tell
One or more in temperature 80, polysorbate85；The poloxamer be selected from Poloxamer 122, Poloxamer 188,
One or more in Poloxamer 237, Poloxamer 338, Poloxamer 407.
In another embodiment of the invention, 3-n-butylphthalide injection composition is：Comprising butylphenyl phthaleine or levo butyl phthalide, gather
Glycols surfactant, phosphatide, polyoxyethylene sorbitan fatty acid ester class and water for injection, in terms of 100mL, each group
Point percentage by weight be：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Polyethylene glycols surfactant | 0.04~10.0 |
| Phosphatide | 0.01~10.0 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.02~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Polyethylene glycols surfactant | 0.4~6.0 |
| Phosphatide | 0.05~6.0 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.1~6.0 |
| Water for injection | Surplus |
The polyethylene glycols surfactant is selected from：HS15, polyethylene glycol-VE carbonic acid
Ester, PEG-THS（Polyethylene glycol-VE succinates）、PEG-DSPE（PEG2000-DSPE）、PEG-
CHS（PEG-CHOL succinate）、PEG-CHM（PEG-CHM）, PEG-CHOL sulfuric acid
One or more in ester；The phosphatide is selected from egg yolk lecithin, soybean lecithin, PC（Phosphatidyl choline）、EPG（Lecithin
Acyl glycerine）、SPG（Soy phosphatidylglycerol）、DOPC（DOPC）、DOPG（DOPG）、
DPPC（DPPC）、DPPG（DPPG）、DMPC（Dimyristoyl phosphatidyl choline）、
DMPG（GLYCEROL,DIMYRISTOYL PHOSPHATIDYL）、DLPC（DLPC）、DLPG（PE）,
One or more preferably in egg yolk lecithin, soybean lecithin；The polyoxyethylene sorbitan fatty acid ester class choosing
From：One or more in polysorbas20, polysorbate40, polysorbate60, polysorbate65, Tween 80, polysorbate85.
In another embodiment of the invention, 3-n-butylphthalide injection composition is：Comprising butylphenyl phthaleine or levo butyl phthalide, gather
Glycols surfactant, poloxamer, polyoxyethylene sorbitan fatty acid ester class and water for injection, in terms of 100mL,
The percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Polyethylene glycols surfactant | 0.04~10.0 |
| Poloxamer | 0.01~10.0 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.02~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Polyethylene glycols surfactant | 0.4~6.0 |
| Poloxamer | 0.05~6.0 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.1~6.0 |
| Water for injection | Surplus |
The polyethylene glycols surfactant is selected from：HS15, polyethylene glycol-VE carbonic acid
Ester, PEG-THS（Polyethylene glycol-VE succinates）、PEG-DSPE（PEG2000-DSPE）、PEG-
CHS（PEG-CHOL succinate）、PEG-CHM（PEG-CHM）, PEG-CHOL sulfuric acid
One or more in ester；The poloxamer be selected from Poloxamer 122, Poloxamer 188, Poloxamer 237,
One or more in Poloxamer 338, Poloxamer 407；The polyoxyethylene sorbitan fatty acid ester class choosing
From：One or more in polysorbas20, polysorbate40, polysorbate60, polysorbate65, Tween 80, polysorbate85.
In another embodiment of the invention, 3-n-butylphthalide injection composition is：Include butylphenyl phthaleine or levo butyl phthalide, phosphorus
Fat, poloxamer, polyoxyethylene sorbitan fatty acid ester class and water for injection, in terms of 100mL, the weight percent of each component
Than for：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Phosphatide | 0.01~10.0 |
| Poloxamer | 0.01~10.0 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.02~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Phosphatide | 0.05~6.0 |
| Poloxamer | 0.05~6.0 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.1~6.0 |
| Water for injection | Surplus |
The phosphatide is selected from egg yolk lecithin, soybean lecithin, PC（Phosphatidyl choline）、EPG（EPG）、
SPG（Soy phosphatidylglycerol）、DOPC（DOPC）、DOPG（DOPG）、DPPC（Two palms
Phosphatidyl choline）、DPPG（DPPG）、DMPC（Dimyristoyl phosphatidyl choline）、DMPG（Two Pork and beans
Cool acyl phosphatidyl glycerol）、DLPC（DLPC）、DLPG（PE）, preferably yolk
One or more in lecithin, soybean lecithin；The poloxamer be selected from Poloxamer 122, Poloxamer 188,
One or more in Poloxamer 237, Poloxamer 338, Poloxamer 407；The Polyoxyethylene sorbitan
Polyol fatty acid esters are selected from：One or more in polysorbas20, polysorbate40, polysorbate60, polysorbate65, Tween 80, polysorbate85.
In another embodiment of the invention, 3-n-butylphthalide injection composition is：Include butylphenyl phthaleine or levo butyl phthalide, phosphorus
Fat, poloxamer, polyethylene glycols surfactant and water for injection, in terms of 100mL, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Phosphatide | 0.01~10.0 |
| Poloxamer | 0.01~10.0 |
| Polyethylene glycols surfactant | 0.02~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Phosphatide | 0.05~6.0 |
| Poloxamer | 0.05~6.0 |
| Polyethylene glycols surfactant | 0.1~6.0 |
| Water for injection | Surplus |
The phosphatide is selected from egg yolk lecithin, soybean lecithin, PC（Phosphatidyl choline）、EPG（EPG）、
SPG（Soy phosphatidylglycerol）、DOPC（DOPC）、DOPG（DOPG）、DPPC（Two palms
Phosphatidyl choline）、DPPG（DPPG）、DMPC（Dimyristoyl phosphatidyl choline）、DMPG（Two Pork and beans
Cool acyl phosphatidyl glycerol）、DLPC（DLPC）、DLPG（PE）, preferably yolk
One or more in lecithin, soybean lecithin；The poloxamer be selected from Poloxamer 122, Poloxamer 188,
One or more in Poloxamer 237, Poloxamer 338, Poloxamer 407；Live on the polyethylene glycols surface
Property agent is selected from：HS15, polyethylene glycol-VE carbonic esters, PEG-THS（Polyethylene glycol-VE butanedioic acids
Ester）、PEG-DSPE（PEG2000-DSPE）、PEG-CHS（PEG-CHOL succinate）、
PEG-CHM（PEG-CHM）, one or more in PEG-CHOL sulfuric ester.
In another embodiment of the invention, 3-n-butylphthalide injection composition is：Include butylphenyl phthaleine or levo butyl phthalide, phosphorus
Fat, poloxamer, polyethylene glycols surfactant, polyoxyethylene sorbitan fatty acid ester class and water for injection, with
100mL is counted, and the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.02~2.5 |
| Phosphatide | 0.01~10.0 |
| Poloxamer | 0.01~10.0 |
| Polyethylene glycols surfactant | 0.02~10.0 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.02~10.0 |
| Water for injection | Surplus |
Preferably, the percentage by weight of each component is：
| Component | Percentage by weight % |
| Butylphenyl phthaleine or levo butyl phthalide | 0.1~1.25 |
| Phosphatide | 0.05~6.0 |
| Poloxamer | 0.05~6.0 |
| Polyethylene glycols surfactant | 0.1~6.0 |
| Polyoxyethylene sorbitan fatty acid ester class | 0.1~6.0 |
| Water for injection | Surplus |
The phosphatide is selected from egg yolk lecithin, soybean lecithin, PC（Phosphatidyl choline）、EPG（EPG）、
SPG（Soy phosphatidylglycerol）、DOPC（DOPC）、DOPG（DOPG）、DPPC（Two palms
Phosphatidyl choline）、DPPG（DPPG）、DMPC（Dimyristoyl phosphatidyl choline）、DMPG（Two Pork and beans
Cool acyl phosphatidyl glycerol）、DLPC（DLPC）、DLPG（PE）, preferably yolk
One or more in lecithin, soybean lecithin；The poloxamer be selected from Poloxamer 122, Poloxamer 188,
One or more in Poloxamer 237, Poloxamer 338, Poloxamer 407；Live on the polyethylene glycols surface
Property agent is selected from：HS15, polyethylene glycol-VE carbonic esters, PEG-THS（Polyethylene glycol-VE butanedioic acids
Ester）、PEG-DSPE（PEG2000-DSPE）、PEG-CHS（PEG-CHOL succinate）、
PEG-CHM（PEG-CHM）, one or more in PEG-CHOL sulfuric ester；The polyoxyethylene
Fatty acid esters of sorbitan class is selected from：One kind in polysorbas20, polysorbate40, polysorbate60, polysorbate65, Tween 80, polysorbate85 or
It is a variety of.
Another aspect of the present invention additionally provides a kind of preparation method of the 3-n-butylphthalide injection, comprises the following steps：
1. weighing the surfactant of recipe quantity, it is dissolved in injection water；
2. adding butylphenyl phthaleine or derivatives thereof into step 1. solution, it is sufficiently mixed, obtains settled solution；
3. the stabilizer of recipe quantity, pH adjusting agent optionally, are added into step 2. solution；
4. 2. or 3. adding activated carbon in solution to step, to stir, filtering carbon removal is degerming,
5. optionally step 4. solution direct packaging, sterilizing, or add freeze drying protectant packing, are freezed, obtain fourth of the present invention
Phthalide parenteral solution.
Wherein：1. it is 20 ~ 60 DEG C that step controls solution temperature；2. it is 20 ~ 30 DEG C that step controls solution temperature；
4. activated carbon percentage composition is 0.1 ~ 0.5% to step.
The 3-n-butylphthalide injection advantage of the present invention is：1. prepared preparation can effectively cover the peat-reek of butylphenyl phthaleine；
2. the prepared quality of the pharmaceutical preparations is stable；3. butylphthalide content is high, the preparation of small size can be distributed into, can be not only used for intravenous injection again can
For intramuscular injection, meet clinical administration demand；4. preparation technology is simple, strong operability, beneficial to industrialization.
Embodiment
Content of the present invention is further described in detail below in conjunction with specific embodiment.
The 3-n-butylphthalide injection of embodiment 1（Liquid drugs injection）：Include butylphenyl phthaleine, soybean lecithin and water for injection, three's prescription
Dosage see the table below：
In terms of 100mL：
| Name of material | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 0.25g | 0.25 |
| Soybean lecithin | 4g | 4 |
| Injection water | Moisturizing is to 100ml |
Preparation technology：At 40 ~ 60 DEG C, soybean lecithin is dissolved in about 90ml injection waters, butylphenyl phthaleine is slowly added dropwise, fully
Stirring, is smashed with high pressure homogenizer, and control particle diameter is less than 50 nanometers, is obtained supernatant liquid, moisturizing to 100ml, is added 0.1% and live
Property charcoal stir 30 minutes, filter carbon removal, it is degerming, packing, every 10ml, sterilizing.
The 3-n-butylphthalide injection of embodiment 2（Liquid drugs injection）：Include butylphenyl phthaleine, HS15 and injection
Water, three's prescription dosage see the table below：
| Name of material | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 0.25g | 0.25 |
| HS15 | 1g | 1 |
| Injection water | Moisturizing is to 100ml |
Preparation technology：At 20 ~ 30 DEG C, HS15 is dissolved in about 90ml injection waters, slowly
Butylphenyl phthaleine is added dropwise, is sufficiently stirred, liquid level does not have oil droplet appearance, obtains supernatant liquid, moisturizing to 100ml, adds 0.2% activated carbon
Stirring 30 minutes, carbon removal is filtered, degerming, packing, every 10ml, sterilizing.
The 3-n-butylphthalide injection of embodiment 3（Freeze-dried powder）：Comprising butylphenyl phthaleine, HS15 and
Water for injection, three's prescription dosage see the table below：
| Name of material | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 0.5g | 0.5 |
| HS15 | 2g | 2 |
| Mannitol | 6g | 6 |
| Glucose | 1.5g | 1.5 |
| Injection water | Moisturizing is to 100ml |
Preparation technology：At 20 ~ 30 DEG C, HS15 is dissolved in about 90ml injection waters, slowly
Butylphenyl phthaleine is added dropwise, is sufficiently stirred, liquid level does not have oil droplet appearance, adds the dissolving of sweet dew alcohol and glucose, obtains supernatant liquid, moisturizing
To 100ml, add 0.1% activated carbon and stir 30 minutes, filter carbon removal, it is degerming, packing, every 5ml, freeze.
The 3-n-butylphthalide injection of embodiment 4（Liquid drugs injection）：Include butylphenyl phthaleine, Tween 80 and water for injection, three's prescription dosage
It see the table below：
| Name of material | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 0.25g | 0.25 |
| Tween 80 | 2g | 2 |
| Injection water | Moisturizing is to 100ml |
Preparation technology：At 20 ~ 30 DEG C, Tween 80 is dissolved in about 90ml injection waters, butylphenyl phthaleine is slowly added dropwise, fully stirs
Mix, liquid level does not have oil droplet appearance, obtains supernatant liquid, moisturizing to 100ml, adds 0.2% activated carbon and stir 30 minutes, cross and filter out
Charcoal, degerming, packing, every 10ml, sterilizing.
The 3-n-butylphthalide injection of embodiment 5（Liquid drugs injection）：Comprising butylphenyl phthaleine, Poloxamer 188 and water for injection, at three
Square dosage see the table below：
| Name of material | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 0.25g | 0.25 |
| Poloxamer 188 | 3g | 3 |
| Injection water | Moisturizing is to 100ml |
Preparation technology：At 20 ~ 30 DEG C, Poloxamer 188 is dissolved in about 90ml injection waters, butylphenyl phthaleine is slowly added dropwise,
It is sufficiently stirred, liquid level does not have oil droplet appearance, obtains supernatant liquid, moisturizing to 100ml, adds 0.2% activated carbon and stir 30 minutes,
Carbon removal is filtered, degerming, packing, every 10ml, sterilizing.
The 3-n-butylphthalide injection of embodiment 6（Liquid drugs injection）：Include butylphenyl phthaleine, HS15, yolk
Lecithin and water for injection, three's prescription dosage see the table below：
| Name of material | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 0.5g | 0.5 |
| HS15 | 3g | 3 |
| Egg yolk lecithin | 0.1g | 0.1 |
| Injection water | Moisturizing is to 100ml |
Preparation technology：At 40 ~ 60 DEG C, HS15, egg yolk lecithin are dissolved in about 90ml notes
In jetting, 20 ~ 30 DEG C are cooled to, butylphenyl phthaleine is slowly added dropwise, is sufficiently stirred, liquid level does not have oil droplet appearance, obtains supernatant liquid, mends
Water adds 0.1% activated carbon and stirred 30 minutes, filtering carbon removal is degerming, packing, every 5ml, sterilizes to 100ml.
The 3-n-butylphthalide injection of embodiment 7（Liquid drugs injection）：Include butylphenyl phthaleine, HS15, tween
80 and water for injection, prescription dosage see the table below：
| Name of material | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 0.5g | 0.5 |
| HS15 | 2.4g | 2.4 |
| Tween 80 | 0.1g | 0.1 |
| Injection water | Moisturizing is to 100ml |
Preparation technology：At 40 ~ 60 DEG C, HS15, Tween 80 are dissolved in about 90ml injection waters
In, 20 ~ 30 DEG C are cooled to, butylphenyl phthaleine is slowly added dropwise, is sufficiently stirred, liquid level does not have oil droplet appearance, obtains supernatant liquid, moisturizing is extremely
100ml, add 0.1% activated carbon and stir 30 minutes, filter carbon removal, degerming, packing, every 5ml, sterilizing.
The 3-n-butylphthalide injection of embodiment 8（Liquid drugs injection）：Include butylphenyl phthaleine, Tween 80, egg yolk lecithin and water for injection, place
Square dosage see the table below：
| Name of material | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 0.25g | 0.25 |
| Tween 80 | 1.8g | 1.8 |
| Egg yolk lecithin | 0.5g | 0.5 |
| Injection water | Moisturizing is to 100ml |
Preparation technology：At 30 ~ 60 DEG C, Tween 80, egg yolk lecithin are dissolved in about 90ml injection waters, are cooled to 20 ~ 30
DEG C, butylphenyl phthaleine is slowly added dropwise, is sufficiently stirred, liquid level does not have oil droplet appearance, obtains supernatant liquid, moisturizing to 100ml, adds 0.5%
Activated carbon stirs 30 minutes, filters carbon removal, degerming, packing, every 10ml, sterilizing.
The 3-n-butylphthalide injection of embodiment 9（Liquid drugs injection）：Include butylphenyl phthaleine, egg yolk lecithin, Poloxamer 188 and injection
With water, in terms of 100mL, the percentage by weight of each component is：
| Component | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 0.25g | 0. 25 |
| Egg yolk lecithin | 0.1g | 0. 1 |
| Poloxamer 188 | 2.6g | 2.6 |
| Water for injection | Moisturizing is to 100ml |
Preparation technology：At 30 ~ 60 DEG C, Poloxamer 188, egg yolk lecithin are dissolved in about 90ml injection waters, cooled
To 20 ~ 30 DEG C, butylphenyl phthaleine being slowly added dropwise, is sufficiently stirred, liquid level does not have oil droplet appearance, obtains supernatant liquid, moisturizing to 100ml,
Add 0.5% activated carbon to stir 30 minutes, filter carbon removal, degerming, packing, every 10ml, sterilizing.
The 3-n-butylphthalide injection of embodiment 10（Liquid drugs injection）：Comprising butylphenyl phthaleine, HS15,
Poloxamer 188 and water for injection, in terms of 100mL, the percentage by weight of each component is：
| Component | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 0.25g | 0. 25 |
| HS15 | 1g | 1 |
| Poloxamer 188 | 1g | 1 |
| Water for injection | Moisturizing is to 100ml |
Preparation technology：At 30 ~ 60 DEG C, HS15, Poloxamer 188 are dissolved in about 90ml
In injection water, 20 ~ 30 DEG C being cooled to, butylphenyl phthaleine is slowly added dropwise, is sufficiently stirred, liquid level does not have oil droplet appearance, obtains supernatant liquid,
Moisturizing adds 0.5% activated carbon and stirred 30 minutes, filtering carbon removal is degerming, packing, every 10ml, sterilizes to 100ml.
The 3-n-butylphthalide injection of embodiment 11（Liquid drugs injection）：Include butylphenyl phthaleine, Tween 80, Poloxamer 188 and injection
Water, in terms of 100mL, the percentage by weight of each component is：
| Component | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 0.25g | 0. 25 |
| Tween 80 | 1g | 1 |
| Poloxamer 188 | 2g | 2 |
| Water for injection | Moisturizing is to 100ml |
Preparation technology：At 30 ~ 60 DEG C, Tween 80, Poloxamer 188 are dissolved in about 90ml injection waters, it is cooled to 20 ~
30 DEG C, butylphenyl phthaleine is slowly added dropwise, is sufficiently stirred, liquid level does not have oil droplet appearance, obtains supernatant liquid, moisturizing to 100ml, adds
0.5% activated carbon stirs 30 minutes, filters carbon removal, degerming, packing, every 10ml, sterilizing.
The 3-n-butylphthalide injection of embodiment 12（Liquid drugs injection）：Include butylphenyl phthaleine, Poloxamer 188, egg yolk lecithin, tween
80 and water for injection, prescription dosage see the table below：
| Name of material | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 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 | Moisturizing is to 100ml |
Preparation technology：At 30 ~ 60 DEG C, Poloxamer 188, Tween 80, egg yolk lecithin are dissolved in about 90ml injection waters
In, 20 ~ 30 DEG C are cooled to, butylphenyl phthaleine is slowly added dropwise, is sufficiently stirred, liquid level does not have oil droplet appearance, obtains supernatant liquid, moisturizing is extremely
100ml, add 0.5% activated carbon and stir 30 minutes, filter carbon removal, degerming, packing, every 10ml, sterilizing.
The 3-n-butylphthalide injection of embodiment 13（Liquid drugs injection）：Include butylphenyl phthaleine, HS15, tween
80th, Poloxamer 188 and water for injection, prescription dosage see the table below：
| Name of material | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 0.25g | 0.25 |
| HS15 | 1g | 1 |
| Tween 80 | 0.4g | 0.4 |
| Poloxamer 188 | 0.2g | 0.2 |
| Injection water | Moisturizing is to 100ml |
Preparation technology：It is at 30 ~ 60 DEG C, HS15, Tween 80, Poloxamer 188 is molten
In about 90ml injection waters, 20 ~ 30 DEG C are cooled to, butylphenyl phthaleine is slowly added dropwise, is sufficiently stirred, liquid level does not have oil droplet appearance, obtains
Supernatant liquid, moisturizing to 100ml, add 0.5% activated carbon and stir 30 minutes, filter carbon removal, it is degerming, packing, every 10ml, go out
Bacterium.
The 3-n-butylphthalide injection of embodiment 14（Liquid drugs injection）：Include butylphenyl phthaleine, HS15, yolk
Lecithin, Tween 80 and water for injection, prescription dosage see the table below：
| Name of material | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 1.25g | 1.25 |
| HS15 | 4g | 4 |
| Egg yolk lecithin | 0.1g | 0.1 |
| Tween 80 | 1.2g | 1.2 |
| Injection water | Moisturizing is to 100ml |
Preparation technology：At 40 ~ 60 DEG C, HS15, egg yolk lecithin and Tween 80 are dissolved in
In about 90ml injection waters, 20 ~ 30 DEG C are cooled to, butylphenyl phthaleine is slowly added dropwise, is sufficiently stirred, liquid level does not have oil droplet appearance, obtains clear
Clear liquid body, moisturizing to 100ml, add 0.5% activated carbon and stir 30 minutes, filter carbon removal, degerming, packing, every 2ml, sterilizing.
The 3-n-butylphthalide injection of embodiment 15（Liquid drugs injection）：Include butylphenyl phthaleine, HS15, yolk
Lecithin, Tween 80, Poloxamer 188 and water for injection, prescription dosage see the table below：
| Name of material | Recipe quantity | Percentage by weight % |
| Butylphenyl phthaleine | 1.25g | 1.25 |
| HS15 | 4g | 4 |
| Egg yolk lecithin | 0.1g | 0.1 |
| Tween 80 | 0.8g | 0.8 |
| Poloxamer 188 | 0.1g | 0.1 |
| Injection water | Moisturizing is to 100ml |
Preparation technology：At 40 ~ 60 DEG C, by HS15, egg yolk lecithin, Tween 80 and
Poloxamer 188 is dissolved in about 90ml injection waters, is cooled to 20 ~ 30 DEG C, butylphenyl phthaleine is slowly added dropwise, be sufficiently stirred, liquid level does not have
There is oil droplet appearance, obtain supernatant liquid, moisturizing to 100ml, add 0.5% activated carbon and stir 30 minutes, filter carbon removal, it is degerming, point
Dress, every 2ml, sterilizing.
The sample stability of embodiment 16 is tested
The sample prepared to embodiment 1 ~ 15 exists（40 DEG C, RH75%）Place, carry out stability experiment investigation, it is as a result as follows：
Continued 1：
Continued 2：
As a result show, 3-n-butylphthalide injection of the present invention deposits 2 years steady qualities for a long time.
The sample compatibility stability of embodiment 17 is tested
The sample prepared to embodiment 1 ~ 15, noted respectively with the sodium chloride injections of 100ml 0.9% and the glucose of 100ml 5%
It is dilute solution to penetrate liquid, by 40 DEG C of placements of solution after dilution, investigates the stability under the conditions of its Clinical practice：
Continued 1：
Continued 2：
Continued 3：
Continued 4：
Continued 5：
As a result show, 3-n-butylphthalide injection of the present invention is stable in 8 hours under the conditions of Clinical practice, and adapting to clinical application needs
Will.
The vascular stimulation test of embodiment 18
1st, experimental design：Sample prepared by embodiment 1 ~ 15, rabbit auricular vein drug administration by injection, dosage 5mL.
2nd, medication
Healthy new zealand rabbit 30 is selected, respectively at the left auricular vein injection test medicine of rabbit, in bodies such as auris dextra intravenous injections
Long-pending sodium chloride injection compares.After 30 rabbits give test medicine successively, then 0.9% sodium chloride injection is given respectively
5mL, one time a day, for three days on end.Respectively weighed 1 time within 48 hours and 14 days before administration and after last dose.
3rd, overview and animal materials
Observed before daily administration and record animal and the reaction at intravascular injection position, 48 hours after last dose, put respectively
Blood puts to death 1 animal of test medicine, after visually observing and recording the reaction of vascular tissue, subtracts lower double rabbit ears from the ear portion（First
Subtract left ear, after cut auris dextra, and mark）, then one section of rabbit ear polupus of clip is fixed in 10% neutral formalin solution respectively（Sample
Be about 8cm, wide about 1cm, distal end otch the first pinprick of distance is about at 0.5cm, proximal part otch according to the 3rd pinprick about at 2cm,
Hanging wire end is proximal part）.1 animal for respectively leaving test medicine continues observation to 14 days after last dose, carries out pathologic finding.
Using the first pinprick as boundary, one section is distally cut；Using the 3rd pinprick as boundary, proximal part cuts two sections；Blood vessel is crosscutting during film-making,
Routine paraffin wax flaking, slice thickness are about 4 ~ 5 μm, then carry out histopathologic examination.
4th, result judgement
According to visually observing comprehensive descision is carried out with the result of pathologic finding.Visually observed before daily administration and record animal
The reaction at intravascular injection position, the Some Animals administration side and control sides rabbit ear inserting needle portion of the visible test medicine of naked eyes during administration
Survey and take on a red color in the vascular epidermis of position, area is by 0.1cm × 0.2cm to 0.2cm × 1.0cm.It is tested 48 hours after last dose
The bilateral rabbit ear vessel profile of 2 rabbits of medicine is more visible, and rabbit ear thickness is uniform, has no obvious change.14 days after last dose
15 rabbits of cut open inspection test medicine, bilateral rabbit ear vessel profile is more visible, and rabbit ear thickness is uniform, has no obvious change.
15 rabbits of test medicine, 6 rabbits of 48 hours cut open inspections and remaining test medicine after last dose recovered at 2 weeks
Phase terminates rear cut open inspection, and histopathologic examination, which is showed no vascular tissue, the notable irritative responses such as denaturation or necrosis.
The muscle irritation of embodiment 19 is tested
1st, experimental design：Sample prepared by embodiment 1 ~ 15, rabbit quadriceps muscle of thigh intramuscular administration, dosage 1mL.
2nd, medication and Germicidal efficacy
Each sample correspondingly takes the new zealand rabbit 2 of health, and with aseptic manipulation, quadriceps muscle of thigh is intramuscular on the left of rabbit
Test medicine is injected, is compared in the isometric sodium chloride injection of right side quadriceps muscle of thigh intramuscular injection.One time a day, continuous 3
My god.Observed every time before administration and record the reaction of animal and injection site.48 hours after last dose, test medicine 1 is respectively taken
Animal, sacrificed by exsanguination, exposure quadriceps muscle of thigh is dissected, it is longitudinally slit, visually observe and record the stimulate the reaction situation of injection site,
Then injection site muscle is made into histopathologic examination.1 animal for respectively leaving reagent thing continues to observe to last dose
14 days, carry out injection site pathologic finding.
3rd, result judgement
Visually observed after last dose after 48 hours and 14 days, side is administered and control sides have no significant change, injection site
Table, the high resilience of deep musculature quality, gloss.
Pathological observation after 48 hours and 14 days after last dose, is administered side and control sides muscular tissue structure is normal, and flesh is fine
Tie up marshalling.
Visually observe and show with pathological observation result, 3-n-butylphthalide injection sample of the present invention to new zealand rabbit injection site not
See that the obvious irritations such as degeneration necrosis change.
To sum up, 3-n-butylphthalide injection small volume of the invention, preparation technology is simple to operation, steady quality, to blood vessel and
Muscle is nonirritant, safe, meets clinical application demand.
Claims (21)
1. a kind of 3-n-butylphthalide injection, comprising butylphenyl phthaleine, surfactant and water for injection, the butylphenyl phthaleine, surfactant
And the weight ratio of water for injection is：1:2~50:50~500, the surfactant is selected from：Polyethylene glycols surfactant,
Or polyethylene glycols surfactant and phosphatide, polyoxyethylene sorbitan fatty acid ester class, one kind in poloxamer or
Several mixtures；
Wherein：
The polyethylene glycols surfactant is selected from：HS15；
The phosphatide is selected from：Egg yolk lecithin, soybean lecithin；
The polyoxyethylene sorbitan fatty acid ester class is selected from：Tween 80；
The poloxamer is selected from：Poloxamer 188.
2. 3-n-butylphthalide injection as claimed in claim 1, it is characterised in that：The butylphenyl phthaleine is dl-3-n-butylphthalide or left-handed fourth
Phthalide.
3. 3-n-butylphthalide injection as claimed in claim 1, it is characterised in that：Butylphenyl phthaleine, surfactant and water for injection
Weight ratio is：1:3~20:80~400.
4. 3-n-butylphthalide injection as claimed in claim 1, it is characterised in that：In the HS15
Polyethylene glycol molecular weight be 300~30000.
5. 3-n-butylphthalide injection as claimed in claim 1, it is characterised in that：The 3-n-butylphthalide injection also comprising stabilizer,
PH adjusting agent.
6. 3-n-butylphthalide injection as claimed in claim 5, it is characterised in that：The stabilizer is selected from nitrogen, inert gas, resisted
One or more in oxygen agent or EDTA-2Na.
7. 3-n-butylphthalide injection as claimed in claim 6, it is characterised in that：The antioxidant is in tocopherol, vitamin C
One or two.
8. 3-n-butylphthalide injection as claimed in claim 5, it is characterised in that：The pH adjusting agent is selected from organic acids and base, inorganic
Soda acid or combinations thereof.
9. 3-n-butylphthalide injection as claimed in claim 8, it is characterised in that：The organic acid is selected from citric acid, lactic acid, rich horse
Acid, tartaric acid, acetic acid, gluconic acid, lactobionic acid, sorbic acid, butanedioic acid, maleic acid, oxalic acid, formic acid, benzene sulfonic acid, benzoic acid,
One or more in glutamic acid, lysine, aspartic acid；The inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrogen bromine
One or more in acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate.
10. the butylphenyl phthaleine freeze-dried powder made of the 3-n-butylphthalide injection described in claim 1.
11. butylphenyl phthaleine freeze-dried powder as claimed in claim 10, it is characterised in that：Also include freeze drying protectant.
12. butylphenyl phthaleine freeze-dried powder as claimed in claim 11, it is characterised in that：The freeze drying protectant is selected from malt
One or more of combinations in sugar, mannitol, glucose.
13. 3-n-butylphthalide injection as claimed in claim 1, it is characterised in that：The 3-n-butylphthalide injection includes racemization butylbenzene
Phthalein or levo butyl phthalide, polyethylene glycols surfactant and water for injection, in terms of 100mL, the percentage by weight of each component is：
14. 3-n-butylphthalide injection as claimed in claim 13, it is characterised in that：The 3-n-butylphthalide injection, in terms of 100mL,
The percentage by weight of each component is：
15. 3-n-butylphthalide injection as claimed in claim 1, it is characterised in that：The 3-n-butylphthalide injection includes racemization butylbenzene
Phthalein or levo butyl phthalide, phosphatide, polyethylene glycols surfactant and water for injection, in terms of 100mL, the weight percent of each component
Than for：
16. 3-n-butylphthalide injection as claimed in claim 15, it is characterised in that：The 3-n-butylphthalide injection, in terms of 100mL,
The percentage by weight of each component is：
17. 3-n-butylphthalide injection as claimed in claim 1, it is characterised in that：The 3-n-butylphthalide injection includes racemization butylbenzene
Phthalein or levo butyl phthalide, polyethylene glycols surfactant, polyoxyethylene sorbitan fatty acid ester class and water for injection, with
100mL is counted, and the percentage by weight of each component is：
18. 3-n-butylphthalide injection as claimed in claim 17, it is characterised in that：The 3-n-butylphthalide injection, in terms of 100mL,
The percentage by weight of each component is：
19. 3-n-butylphthalide injection as claimed in claim 1, it is characterised in that：The 3-n-butylphthalide injection includes racemization butylbenzene
Phthalein or levo butyl phthalide, polyethylene glycols surfactant, poloxamer and water for injection, in terms of 100mL, the weight of each component
Percentage is：
20. 3-n-butylphthalide injection as claimed in claim 19, it is characterised in that：The 3-n-butylphthalide injection, in terms of 100mL,
The percentage by weight of each component is：
21. a kind of preparation method of 3-n-butylphthalide injection as claimed in claim 1, comprises the following steps：
1. weighing the surfactant of recipe quantity, it is dissolved in injection water；
2. adding butylphenyl phthaleine into step 1. solution, it is sufficiently mixed, obtains settled solution；
3. the stabilizer of recipe quantity, pH adjusting agent optionally, are added into step 2. solution；
4. 2. or 3. adding activated carbon in solution to step, stir, filtering carbon removal is degerming；
5. step 4. solution direct packaging, sterilizing is optionally obtained into 3-n-butylphthalide injection.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711075087.9A CN107970208B (en) | 2012-06-27 | 2012-06-27 | Butylphthalide injection and preparation method thereof |
| CN201210214131.0A CN103505409B (en) | 2012-06-27 | 2012-06-27 | A kind of 3-n-butylphthalide injection and preparation method thereof |
Applications Claiming Priority (1)
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107970208A (en) * | 2012-06-27 | 2018-05-01 | 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 |
| RU2812533C1 (en) * | 2020-03-20 | 2024-01-30 | СиЭсПиСи ЭнБиПи ФАРМАСЬЮТИКАЛ КО., ЛТД | Use of butyl phthalide and its derivatives |
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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 |
| WO2021185356A1 (en) * | 2020-03-20 | 2021-09-23 | 石药集团恩必普药业有限公司 | Use of butylphthalide and derivative thereof |
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| 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 |
| 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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| CN1375288A (en) * | 2002-05-13 | 2002-10-23 | 周桂荣 | Composite medicine for treating cerebrovascular diseases |
| US20060166931A1 (en) * | 2002-08-21 | 2006-07-27 | Niu Zhan-Qi | Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparation and the use thereof |
| CN1290491C (en) * | 2004-09-20 | 2006-12-20 | 周桂荣 | Medicine for treating acute ischemic cerebral apoplexy and its preparing method |
| 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 |
| 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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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107970208A (en) * | 2012-06-27 | 2018-05-01 | 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 |
| CN107970208B (en) * | 2012-06-27 | 2021-01-19 | 石药集团中奇制药技术（石家庄）有限公司 | Butylphthalide injection and preparation method thereof |
| RU2812533C1 (en) * | 2020-03-20 | 2024-01-30 | СиЭсПиСи ЭнБиПи ФАРМАСЬЮТИКАЛ КО., ЛТД | Use of butyl phthalide and its derivatives |
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| Publication number | Publication date |
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| CN103505409A (en) | 2014-01-15 |
| CN107970208B (en) | 2021-01-19 |
| CN107970208A (en) | 2018-05-01 |
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