CN104414981A - Freeze-dried hydroxyl-pentyl benzoate preparation for injection and preparation method of freeze-dried hydroxyl-pentyl benzoate preparation for injection - Google Patents
Freeze-dried hydroxyl-pentyl benzoate preparation for injection and preparation method of freeze-dried hydroxyl-pentyl benzoate preparation for injection Download PDFInfo
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Abstract
The invention provides a freeze-dried hydroxyl-pentyl benzoate preparation for injection and a preparation method of the freeze-dried hydroxyl-pentyl benzoate preparation for injection. The freeze-dried hydroxyl-pentyl benzoate preparation for injection comprises 2-(alpha-hydroxypentyl) benzoate and adjuvants, wherein the adjuvants consist of an excipient and a pH value adjusting agent. The invention further provides a preparation method of a freeze-dried 2-(alpha-hydroxy-pentyl) benzoate preparation for injection. The preparation method comprises the following steps: (1) selecting raw materials, wherein the raw materials consist of hydroxyl-pentyl benzoate, adjuvants and water, and the adjuvants consist of the excipient and the pH value adjusting agent; (2) dissolving the adjuvants into water to form a solution, and adding the hydroxyl-pentyl benzoate into the solution, wherein the pH value of the solution needs to be controlled in a range of 10.5 to 13.0 before and after the hydroxyl-pentyl benzoate is added into the solution; and (3) carrying out freeze drying on the hydroxyl-pentyl benzoate preparation. According to the invention, the problems that the existing injections contain more impurities, change colors and wither and have poor solubility. The freeze-dried hydroxyl-pentyl benzoate preparation for injection can meet the clinical safety requirement, and hemolysis, stimulation and allergy tests show that the freeze-dried hydroxyl-pentyl benzoate preparation for injection is safe and can be fully accepted by the human body.
Description
Technical field
The invention belongs to field of medicine preparing technology, be specifically related to 2-(ɑ-Hydroxy pentyl) freeze-drying preparation for injection of benzoate and preparation method thereof.
Background technology
Apoplexy (apoplexy) causes brain blood flow to be obstructed caused disease for cerebrovascular occlusion or break, in point ischemic cerebral apoplexy and hemorrhagic apoplexy.Apoplexy is not only with high incidence, high mortality, high disability rate harm people ' s health, and in the paralytic of surviving, the overwhelming majority leaves the sequela such as hemiplegia, aphasia, thus causes CR Critical burden to society and family.Therefore to the control of apoplexy by the whole society is paid close attention to.
2-(Alpha-hydroxy amyl group) benzoate (abbreviation hydroxyl amylbenzene formates, formula I) be the new drug (Chinese patent ZL01109795.7) with independent intellectual property right that institute of Materia Medica,Chinese Academy of Medical Sciences is developed, existing medicine and title to patent transfer Haobang Pharmaceutical Co., Ltd., Yunnan.In being applicable to, the treatment of severe acute cerebral infarction.
(I) 2-(ɑ-Hydroxy pentyl) benzoate
Wherein, M is monovalent metallic ion, and it is potassium ion, sodium ion or lithium ion; Or bivalent metal ion, it is calcium ion, magnesium ion or zinc ion, wherein n=1, or n=2.
Hydroxyl amylbenzene formates converts apoplexy new drug 3-n-butylphthalide (formula II) to mainly through enzyme in gastric acid and blood plasma in vivo and plays pharmacological action.Preclinical metabolism and pharmacokinetics study display hydroxyl amylbenzene formates no matter vein or orally all can be converted into butylphthalide rapidly and fully in vivo.
(II) 3-n-butylphthalide
Butylphthalide is pale yellow oil, and hydroxyl amylbenzene formates is crystalline solid soluble in water.Due to the improvement of physicochemical property, hydroxyl amylbenzene formates overcomes the deficiency that butylphthalide exists, and expands indication, improves curative effect, adds the new varieties for the treatment of acute ischemic cerebral apoplexy medicine.Preclinical pharmacodynamics of San research confirms that hydroxyl amylbenzene formates is the neuroprotective of the anti-acute ischemic cerebral apoplexy of Mutiple Targets; there is blood vessel dilating; increase cerebral blood flow; reduce cerebral infarct volume; antiplatelet aggregation, antithrombus formation; the effect of protective wire mitochondria function and anti-apoptotic, thus improve function of nervous system at multiple target spot.
Meanwhile, due to the improvement of physicochemical property, hydroxyl amylbenzene formates is easy to large-scale purification and produces, and also provides convenience for preparing oral solid formulation and injection or lyophilized preparation.
Chinese patent ZL01109795.7 describes 2-(Alpha-hydroxy amyl group) benzoate is for for the prevention and therapy heart, cerebral ischemia diseases, the heart, cerebral arteries emphraxis, improve the medicine of the disease such as the heart, cerebral microcirculation disturbance, it can containing pharmaceutically connecing the Conventional pharmaceutical carriers awarded, as: starch, sucrose, calcium carbonate, magnesium stearate, polyvinylpyrrolidone, cellulose derivative etc., preferably make tablet, capsule, injection and lyophilized preparation.Various dosage form can be prepared according to the conventional production process of pharmaceutical field.Also describe in embodiment with 2-(Alpha-hydroxy amyl group) benzoate for active component, with appropriate sodium hydroxide, pH value is adjusted to 8.5 ~ 9.5, makes injection or lyophilized preparation.The injection products of this patent Example 16 preparation occurs that impurity increase, variable color, atrophy, solubility are poor, does not have excipient, outward appearance all not molding after lyophilizing in its lyophilized injectable powder of embodiment 17.Describing in Chinese patent CN1594270A embodiment with left-handed 2-(Alpha-hydroxy amyl group) benzoate is for active component, and with appropriate sodium hydroxide, pH value is adjusted to 7.5 ~ 9.5, interpolation sodium chloride or mannitol are as isoosmotic adjusting agent or excipient.2-(Alpha-hydroxy amyl group is prepared according to the prescription in this embodiment) benzoate lyophilized injectable powder, still poor stability, there is variable color, atrophy in product, can not obtain the pharmaceutical formulation product being suitable for injection.
Summary of the invention
The object of the present invention is to provide the freeze-drying preparation for injection of hydroxyl amylbenzene formates, this injection good stability, safe and reliable.
Another object of the present invention is to the preparation method of the freeze-drying preparation for injection providing hydroxyl amylbenzene formates, this preparation method does not need special equipment, is easy to suitability for industrialized production.
Hydroxyl amylbenzene formates injection to have carried out a large amount of prescription screenings when preparing, all occur that impurity increase, variable color, atrophy, solubility are poor, be difficult to all the time solve this technical problem.According to general knowledge, the pH value of injection can not exceed the physiological tolerance scope of people, and general pH value can 4 ~ 9, and intravenous fluid pH value can relax to 3 ~ 9.5 in a small amount.Not by the guidance of any theory, researcher is surprised to find that, when adopting pH value regulator to control hydroxyl amylbenzene formate solution pH value range 10.5 ~ 13.0, the injection of hydroxyl amylbenzene formates shows obvious stability, and its haemolysis, irritate, clinical requirement that sensitivity test all meets injection.
The following hydroxyl amylbenzene formates of the present invention refers to 2-(Alpha-hydroxy amyl group) benzoic salt, specifically comprise the form such as potassium salt, sodium salt, lithium salts or calcium salt, magnesium salt, zinc salt, structural formula is as follows, and wherein potassium salt is used for medicinal be optimum.
2-(ɑ-Hydroxy pentyl) benzoate
Wherein, M is monovalent metallic ion, and it is potassium ion, sodium ion or lithium ion; Or bivalent metal ion, it is calcium ion, magnesium ion or zinc ion, wherein n=1, or n=2.
The invention provides a kind of freeze-drying preparation for injection of hydroxyl amylbenzene formates, said preparation comprises:
A), 2-(Alpha-hydroxy amyl group) benzoate; With
B), adjuvant; Wherein adjuvant comprises excipient, pH value regulator, and pH value regulator consumption in order to the pH value range comprising the solution of water, adjuvant and hydroxyl amylbenzene formates before making lyophilizing is: 10 ~ 13.0.
Further, the consumption weight ratio of adjuvant and hydroxyl amylbenzene formates is 0.1 ~ 20:1.
Further, the amount ratio of adjuvant and hydroxyl amylbenzene formates is 0.2 ~ 15:1.
Further, the amount ratio of adjuvant and hydroxyl amylbenzene formates is 0.3 ~ 10:1
Further, the amount adding pH value regulator is the pH value range of the solution be made up of water, adjuvant and hydroxyl amylbenzene formates before making lyophilizing is 10.5 ~ 13.0.
Further, the amount adding pH value regulator is the pH value range of the solution be made up of water, adjuvant and hydroxyl amylbenzene formates before making lyophilizing is 11 ~ 12.5.
Described pH adjusting agent be selected from organic acid, mineral acid, organic base, inorganic base and/or buffer agent one or more; Wherein, described organic acid or mineral acid are one or more in citric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, lactic acid, maleic acid, acetic acid, tartaric acid, propanoic acid, succinic acid, oxalic acid, malic acid, glutamic acid; Described organic base or inorganic base are one or more in sodium hydroxide, potassium hydroxide, ammonia, amine; Described buffer agent can be selected from sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium citrate, sodium lactate, sodium acetate, sodium carbonate, sodium propionate, natrium malicum one or more, also can obtain corresponding buffer agent by conjugate acid, adding of alkali.
Described excipient be selected from sodium chloride, mannitol, sorbitol, dextran, lactose, sucrose, glucose and lactose one or more, further, preferably adopt in sodium chloride, mannitol, sorbitol, dextran, sucrose, glucose one or more.
Further, also comprise as follows in the adjuvant of described lyophilized injectable powder: one or more in the additive of antibacterial, analgesic, Adjustable viscosity, additive that sensory qualities can be modified etc.
Described antibacterial can select a class in such as parabens, acids (as sorbic acid), cationic surfactant class (as benzalkonium bromide etc.), alcohols (as chlorobutanol, propylene glycol, ethanol etc.) or a few class.
Described analgesic can select benzyl alcohol etc.
The additive of described adjusting viscosity is selected from one or more in lecithin, phospholipid, propylene glycol, Polyethylene Glycol, glycerol, alginic acid, sodium alginate.
The described additive modifying sensory qualities be selected from malic acid, fumaric acid, glycerol, vanillin, Mentholum etc. one or more.
The invention provides a kind of 2-(Alpha-hydroxy amyl group) preparation method of the freeze-drying preparation for injection of benzoate, the method comprises:
1) choose raw material, raw material comprises gets hydroxyl amylbenzene formates, adjuvant, water; Wherein, adjuvant comprises pH adjusting agent, excipient;
2) adjuvant is dissolved in the water is formed after solution, then add hydroxyl amylbenzene formates in this solution; Wherein control hydroxyl amylbenzene formates and add pH value range 10.5 ~ 13.0 that is fashionable and solution after adding; With
3) lyophilizing.
Further, the amount ratio of adjuvant and hydroxyl amylbenzene formates is (0.1 ~ 20): 1.
Further, the amount ratio of adjuvant and hydroxyl amylbenzene formates is (0.2 ~ 15): 1.
Further, the amount ratio of adjuvant and hydroxyl amylbenzene formates is (0.3 ~ 10): 1
Further, control hydroxyl amylbenzene formates add fashionable and after adding the pH value range of solution be 10.5 ~ 13.0.
Further, wherein control hydroxyl amylbenzene formates and add pH value range 11 ~ 12.5 that is fashionable and solution after adding.
Described pH adjusting agent be selected from organic acid, mineral acid, organic base, inorganic base and/or buffer agent one or more; Wherein, described organic acid or mineral acid are one or more in citric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, lactic acid, maleic acid, acetic acid, tartaric acid, propanoic acid, succinic acid, oxalic acid, malic acid, glutamic acid; Described organic base or inorganic base are one or more in sodium hydroxide, potassium hydroxide, ammonia, amine; Described buffer agent can be selected from sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium citrate, sodium lactate, sodium acetate, sodium carbonate, sodium propionate, natrium malicum one or more, also can obtain corresponding buffer agent by conjugate acid, adding of alkali.
Described excipient be selected from sodium chloride, mannitol, sorbitol, dextran, lactose, sucrose, glucose and lactose one or more, further, preferably adopt in sodium chloride, mannitol, sorbitol, dextran, sucrose, glucose one or more.
The amount of described water for injection calculates according to the needs of dissolving hydroxyl amylbenzene formates, adjuvant,
Further, also comprise as follows in the adjuvant of described lyophilized injectable powder: one or more in the additive of antibacterial, analgesic, Adjustable viscosity, additive that sensory qualities can be modified etc.
Described antibacterial can select a class in such as parabens, acids (as sorbic acid), cationic surfactant class (as benzalkonium bromide etc.), alcohols (as chlorobutanol, propylene glycol, ethanol etc.) or a few class.
Described analgesic can select benzyl alcohol etc.
The additive of described adjusting viscosity is selected from one or more in lecithin, phospholipid, propylene glycol, Polyethylene Glycol, glycerol, alginic acid, sodium alginate.
The described additive modifying sensory qualities be selected from malic acid, fumaric acid, glycerol, vanillin, Mentholum etc. one or more.
Described freeze drying process is conventional method, as, the solution added after hydroxyl amylbenzene formates is sub-packed in injection bottle, through pre-freeze (temperature-35 DEG C ~-55 DEG C, 1 ~ 6 hour time), once distil (temperature-10 DEG C ~-30 DEG C, 5 ~ 20 hours time), redrying (temperature 15 DEG C ~ 45 DEG C, 3 ~ 15 hours time), prepares freeze-dried powder injection.
Necessary sterilization steps can also be comprised in described preparation method.
The dosage range of the routine that the dosage of hydroxyl amylbenzene formates can prop up for 1mg ~ 1000mg/, wider dosage can also be adopted according to special needs, specifically, can adjust according to the needs of clinical application, further, preferred dose is that 20mg ~ 500mg/ props up.
In the technical solution used in the present invention, the application target of pH adjusting agent is to reach required pH value range, and its consumption is without special restriction.
When preparing freeze-drying preparation for injection, excipient consumption can adjust according to concrete molding needs, when hydroxyl amylbenzene formates dosage is larger, excipient consumption can less with or need not, when hydroxyl amylbenzene formates dosage is less, the consumption of excipient can be increased, excipient.
Adopt technical scheme of the present invention to prepare containing hydroxyl amylbenzene formates injection pharmaceutical composition and preparation impurity content is low, medicinal liquid clarity is good, good stability.Ejection preparation of the present invention solves prior art injection product and occurs the problems such as impurity increase, variable color, atrophy, solubility difference, and injection of the present invention has and meets clinical safety requirement, haemolysis, irritate, safety that sensitivity test confirms this product, human body can tolerate completely.In addition, the preparation method of the present composition is easy and simple to handle, and technique is simple, is easy to suitability for industrialized production.
Accompanying drawing illustrates:
Fig. 1. embodiment 10 prescription 7 Acceleration study (60 DEG C) 10 days related substance chromatograms
Fig. 2. embodiment 10 prescription 8 Acceleration study (60 DEG C) 10 days related substance chromatograms
Fig. 3. embodiment 10 prescription 9 Acceleration study (60 DEG C) 10 days related substance chromatograms
Fig. 4. embodiment 10 prescription 10 Acceleration study (60 DEG C) 10 days related substance chromatograms
Fig. 5. embodiment 10 prescription 11 Acceleration study (60 DEG C) 10 days related substance chromatograms
Fig. 6. embodiment 10 prescription 12 Acceleration study (60 DEG C) 10 days related substance chromatograms
Fig. 7. embodiment 10 prescription 13 Acceleration study (60 DEG C) 10 days related substance chromatograms
Fig. 8. embodiment 10 prescription 14 Acceleration study (60 DEG C) 10 days related substance chromatograms
Experimental example 1 adjuvant screens
In order to obtain stable injectable agent prescription, the present invention selects different adjuvants to test.
Formula investigated by table 1 adjuvant
Pharmaceutical composition is prepared: by the amount of each formula preparation 10ml, get hydroxyl amylbenzene formates, excipient and buffer salt respectively, add a certain amount of water dissolution, by corresponding pH adjusting agent adjust ph to 9.5, add water and be settled to full dose, shake up, medicinal liquid is sub-packed in injection bottle, sealing.
Study on the stability: aforementioned pharmaceutical compositions is placed in 60 DEG C of constant temperature.Respectively at the 0th, 2,4,8,10 hour sampling and measuring, investigate solution ph, hydroxyl amyl group benzoate degradation situation.
Solution ph measures: get solution to be measured and measure according to Chinese Pharmacopoeia version in 2010 two annex VI H methods.
Major impurity n butylphthalide content: get solution to be measured appropriate, add mobile phase and make the solution containing hydroxyl amylbenzene formates 0.5mg in 1ml, as need testing solution, measure by following chromatographic condition according to high performance liquid chromatography (Chinese Pharmacopoeia version annex V D in 2010), calculate the content of major impurity n butylphthalide by area normalization method.
High performance liquid chromatography chromatographic condition:
Instrument: Agilent1100 and chromatographic work station
Chromatographic column: Kromasil C184.6 × 200mm, 5 μm
Mobile phase: methanol: water (containing 0.2% TBAH and 0.3% triethylamine, phosphoric acid adjust pH to 8) (59:41)
Determined wavelength: 230nm
Column temperature: room temperature
Flow velocity: 1ml/min
Sampling volume: 10 μ L
The medicine adopted in experiment of the present invention and embodiment or reagent all can be buied from market.
The results are shown in Table 2.
Result is investigated in the compatibility of table 2 hydroxyl amylbenzene formates adjuvant
Experiment shows, hydroxyl amylbenzene potassium formate is poor with the customary adjuvant compatibility for injection preparation, through screening in a large number, does not all find suitable adjuvant prescription.
Experimental example 2
The present invention has investigated the steadiness of hydroxyl amylbenzene formates in pH value 4.0 ~ 7.5 solution, and method is as follows:
Get hydroxyl amylbenzene potassium formate appropriate, respectively with the buffer solution that pH value is between 4.0 ~ 7.5, standardize solution.Place in 60 DEG C of constant temperature, get solution to be measured appropriate at interval of 2h, add mobile phase and make the solution containing hydroxyl amylbenzene potassium formate 0.5mg in 1ml, as need testing solution, the chromatographic condition empirically under example 1 measures.Get need testing solution sample introduction 10 μ L, record chromatogram, area normalization method calculates the content of n butylphthalide, the variation tendency of major impurity under investigation condition of different pH.
The results are shown in Table 3.
Hydroxyl amylbenzene potassium formate study on the stability result under the condition of table 3pH4.0 ~ 7.5
Above result shows, in pH value 4 ~ 7.5 scope, this product is unstable.
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, the invention will be further described.But the following example is only used to exemplarily describe technical scheme of the present invention, be not intended to carry out any restriction to protection scope of the present invention.
In following examples, " full dose " refers to the amount finally preparing injection volume, the implication of raw material relates to " mg/ml " unit is to calculate the weight of raw material with the volume of " full dose ", as prepared 1000ml injection, namely mannitol 250mg/ml refers to that mannitol is 250mg as the amount of raw material.
Embodiment 1
Prescription:
Hydroxyl amylbenzene sodium formate 20mg/ml
Mannitol 80mg/ml
Sodium dihydrogen phosphate 20mg/ml
Sodium hydroxide q. s, adjust pH to 10.5
Preparation method: take all adjuvants by prescription amount, adds the water for injection accounting for full dose 80%, is stirred to dissolve, and regulates solution ph to 10.5, is added in above-mentioned adjuvant solution by prescription amount hydroxyl amylbenzene sodium formate, be stirred to dissolve, mixing; Water for injection adds to full dose, then regulates solution ph to 10.5 with the sodium hydroxide solution of 20%; Solution through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of microporous filter membrane aseptic filtration; By the fill of 1ml/ bottle, partly press butyl rubber plug, put lyophilization in freeze dryer; Tamponade, lock aluminium lid, obtains injection hydroxyl amylbenzene formates lyophilized formulations.
Embodiment 2
Prescription:
Hydroxyl amylbenzene potassium formate 60mg/ml
Sodium chloride 50mg/ml
Sodium hydrogen phosphate 10mg/ml
Potassium hydroxide is appropriate, adjust pH to 12.5
Preparation method: take all adjuvants by prescription amount, adds the water for injection accounting for full dose 80%, is stirred to dissolve, and regulates solution ph to 12.5, is added in above-mentioned adjuvant solution by prescription amount hydroxyl amylbenzene potassium formate, be stirred to dissolve, mixing; Water for injection adds to full dose, then regulates solution ph to 12.5 with the potassium hydroxide solution of 20%; Solution through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of microporous filter membrane aseptic filtration; By the fill of 1ml/ bottle, partly press butyl rubber plug, put lyophilization in freeze dryer; Tamponade, lock aluminium lid, obtains injection hydroxyl amylbenzene formates lyophilized formulations.
Embodiment 3
Prescription:
Hydroxyl amylbenzene potassium formate 80mg/ml
Sodium lactate 5mg/ml
Sodium hydroxide q. s, adjust pH to 11.0
Preparation method: take all adjuvants by prescription amount, adds the water for injection accounting for full dose 80%, is stirred to dissolve, and regulates solution ph to 11.0, is added in above-mentioned adjuvant solution by prescription amount hydroxyl amylbenzene potassium formate, be stirred to dissolve, mixing; Water for injection adds to full dose, then regulates solution ph to 11.0 with the sodium hydroxide solution of 20%; Solution through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of microporous filter membrane aseptic filtration; By the fill of 1ml/ bottle, partly press butyl rubber plug, put lyophilization in freeze dryer; Tamponade, lock aluminium lid, obtains injection hydroxyl amylbenzene formates lyophilized formulations.
Embodiment 4
Prescription:
Hydroxyl amylbenzene sodium formate 200mg/ml
Sodium hydroxide q. s, adjust pH to 11.5
Preparation method: take all adjuvants by prescription amount, adds the water for injection accounting for full dose 80%, is stirred to dissolve, and regulates solution ph to 11.5, is added in above-mentioned adjuvant solution by prescription amount hydroxyl amylbenzene sodium formate, be stirred to dissolve, mixing; Water for injection adds to full dose, then regulates solution ph to 11.5 with the sodium hydroxide solution of 20%; Solution through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of microporous filter membrane aseptic filtration; By the fill of 1ml/ bottle, partly press butyl rubber plug, put lyophilization in freeze dryer; Tamponade, lock aluminium lid, obtains injection hydroxyl amylbenzene formates lyophilized formulations.
Embodiment 5
Prescription:
Hydroxyl amylbenzene potassium formate 50mg/ml
Sorbitol 50mg/ml
Sodium carbonate 20mg/ml
Sodium hydroxide q. s, adjust pH to 11.8
Preparation method: take all adjuvants by prescription amount, adds the water for injection accounting for full dose 80%, is stirred to dissolve, and regulates solution ph to 11.8, is added in above-mentioned adjuvant solution by prescription amount hydroxyl amylbenzene potassium formate, be stirred to dissolve, mixing; Water for injection adds to full dose, then regulates solution ph to 11.8 with the sodium hydroxide solution of 20%; Solution through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of microporous filter membrane aseptic filtration; By the fill of 1ml/ bottle, partly press butyl rubber plug, put lyophilization in freeze dryer; Tamponade, lock aluminium lid, obtains injection hydroxyl amylbenzene formates lyophilized formulations.
Embodiment 6
Prescription:
Hydroxyl amylbenzene sodium formate 50mg/ml
Sodium chloride 50mg/ml
Sodium citrate 20mg/ml
Sodium hydroxide q. s, adjust pH to 11.5
Preparation method: take all adjuvants by prescription amount, adds the water for injection accounting for full dose 80%, is stirred to dissolve, and regulates solution ph to 11.5, is added in above-mentioned adjuvant solution by prescription amount hydroxyl amylbenzene sodium formate, be stirred to dissolve, mixing; Water for injection adds to full dose, then regulates solution ph to 11.5 with the sodium hydroxide solution of 20%; Solution through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of microporous filter membrane aseptic filtration; By the fill of 1ml/ bottle, partly press butyl rubber plug, put lyophilization in freeze dryer; Tamponade, lock aluminium lid, obtains injection hydroxyl amylbenzene formates lyophilized formulations.
Embodiment 7
Prescription:
Hydroxyl amylbenzene potassium formate 500mg/ml
Sodium acetate 50mg/ml
Sodium hydroxide q. s, adjust pH to 12.0
Preparation method: take all adjuvants by prescription amount, adds the water for injection accounting for full dose 80%, is stirred to dissolve, and regulates solution ph to 12.0, is added in above-mentioned adjuvant solution by prescription amount hydroxyl amylbenzene potassium formate, be stirred to dissolve, mixing; Water for injection adds to full dose, then regulates solution ph to 12.0 with the sodium hydroxide solution of 20%; Solution through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of microporous filter membrane aseptic filtration; By the fill of 1ml/ bottle, partly press butyl rubber plug, put lyophilization in freeze dryer; Tamponade, lock aluminium lid, obtains injection hydroxyl amylbenzene formates lyophilized formulations.
The quality examination of embodiment 8 example 1 ~ example 7 injection
Example 1 ~ example 7 obtains each 50 of injection hydroxyl amylbenzene formates, investigates the content of its appearance character, solution ph and main degradation products n butylphthalide.
Detection method for quality:
Appearance character: visual method.
Solution ph: get this product 3 bottles, the 5ml that adds water respectively dissolves, and merges, mixing, and (Chinese Pharmacopoeia version in 2010 two annex VI H) measure in accordance with the law.
Major impurity content: get this product in right amount, adds mobile phase and makes the solution containing hydroxyl amylbenzene formates 0.5mg in 1ml, as need testing solution, with aforementioned high-performance liquid chromatography method.
The results are shown in Table 4.
Table 4 quality examination result
| Embodiment | Appearance character | PH value | N butylphthalide % |
| 1 | White cake solid | 10.04 | 0.89 |
| 2 | White cake solid | 12.05 | 0.26 |
| 3 | White powdery solid | 10.56 | 0.55 |
| 4 | Foaming, not molding | 10.67 | 0.42 |
| 5 | White cake solid | 11.25 | 0.38 |
| 6 | White cake solid | 11.06 | 0.31 |
| 7 | White powdery solid | 11.58 | 0.24 |
Embodiment 9
1, injection formula
Prepare hydroxyl amylbenzene potassium formate freeze-drying preparation for injection by table 5 prescription, investigate product appearance and solubility.
Table 5 accessory formula
Preparation technology:
Take all adjuvants by upper table prescription amount, add 80% water for injection, be stirred to dissolve, regulate solution ph to shown scope, prescription amount hydroxyl amylbenzene potassium formate is added in above-mentioned adjuvant solution, is stirred to dissolve, mixing; Water for injection adds to full dose, then regulates solution ph to shown scope with the sodium hydroxide solution of 20%; Solution through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of microporous filter membrane aseptic filtration; By the fill of 1ml/ bottle, partly press butyl rubber plug, put lyophilization in freeze dryer; Tamponade, lock aluminium lid, obtains injection hydroxyl amylbenzene formates lyophilized formulations.
Quality examination:
Prescription 1 ~ 6 obtains each 100 of injection hydroxyl amylbenzene potassium formate lyophilized formulations by preparation technology, and investigate different excipient and consumption thereof, result product appearance and solubility all meet the requirements.
Embodiment 10
1, prescription is in table 6
Table 6 accessory formula
2, preparation technology:
Take corresponding adjuvant by prescription amount, add the water for injection accounting for full dose 80%, be stirred to dissolve, regulate solution ph to shown scope, prescription amount hydroxyl amylbenzene potassium formate is added in above-mentioned adjuvant solution, is stirred to dissolve, mixing; Water for injection adds to full dose, then regulates solution ph to shown scope with the sodium hydroxide solution of 20%; Solution through 0.45 μm of filtering with microporous membrane, then through 0.22 μm of microporous filter membrane aseptic filtration; By the fill of 1ml/ bottle, partly press butyl rubber plug, put lyophilization in freeze dryer; Tamponade, lock aluminium lid, obtains injection hydroxyl amylbenzene formates lyophilized formulations.
3, quality examination:
Prescription 7-14 obtains each 100 of injection hydroxyl amylbenzene potassium formate, is investigated, the results are shown in Table 7 by 60 DEG C of high temperature accelerated tests to its stability.
Table 7 prescription 7-14 study on the stability result
4, prescription 13 quality research experiment further
Adopt prescription 13 and above-mentioned method for making, obtained three batch samples, each 1000, investigate influence factor's test, accelerated test, long term test respectively, understand the stability of product; Investigate the stability of product and infusion, understand the stability of product in process of clinical application; Investigate haemolysis, stimulation, allergy etc., ensure drug safety.
(1) influence factor's test:
Method: the injection hydroxyl amylbenzene formates sample getting Pyrex control injection bottle packaging, place under illumination (4500Lx), high temperature (60 DEG C, 40 DEG C), high humidity (RH90% ± 5%, RH75% ± 5%) condition, 5th, within 10 days, sample respectively, the indexs such as its character, solubility, pH value, related substance, content are investigated, compare with 0 day measurement result, investigate the impacts on this product such as illumination, temperature, humidity.
Measurement result is in table 8.
Table 8 influence factor result of the test
Result shows: injection hydroxyl amylbenzene formates is good at high humidity, illumination and hot conditions stability inferior.
(2) accelerated test:
Get the injection hydroxyl amylbenzene formates (lot number 050718,050722,050726) of Pyrex control injection bottle packaging, in constant temperature and humidity (40 DEG C, RH75%) place in container, respectively at the 0th, sampling in 1,2,3,6 month, the appearance character, basicity, content, related substance etc. of product are measured.In 6 months as a result, every quality index all meets the requirements, and the results are shown in Table 9.
Table 9 Acceleration study (40 DEG C, RH75%) stability result
(3) long term test:
Get the injection hydroxyl amylbenzene formates (lot number 050718,050722,050726) of Pyrex control injection bottle packaging, in constant temperature and humidity (25 DEG C ± 2 DEG C, RH60% ± 10%) place, respectively at the 0th, 3,6,9,12,18,24 and sampling in 36 months, the appearance character, basicity, content, related substance etc. of product are measured.In 36 months as a result, every quality index all meets the requirements, and product can room temperature preservation, has good stability.The results are shown in Table 10.
Table 10 long term test (25 DEG C, RH60%) stability result
(4) with the study on the stability of 0.9% sodium chloride injection compatibility
Sample that room temperature keeps sample for a long time (050718 batch, the 0th, 12,24 months), every bottle adds 50ml0.9% sodium chloride injection, mixes rearmounted climatic chamber (23 DEG C ± 2 DEG C) and places.Measure the stability of compatible solution in 48 hours.The results are shown in Table 11 ~ 13.
Table 11 injection hydroxyl amylbenzene potassium formate (room temperature 0 month) and 0.9% sodium chloride compatibility stability
| Time | Outward appearance | PH value | Insoluble | Related substance |
| （h） | Microgranule | N butylphthalide (%) | ||
| 0 | Colourless clear liquid | 10.85 | Qualified | 0 |
| 4 | Colourless clear liquid | 10.84 | Qualified | 0.50 |
| 8 | Colourless clear liquid | 10.82 | Qualified | 0.79 |
| 24 | Colourless clear liquid | 10.78 | Qualified | 0.75 |
| 48 | Colourless clear liquid | 10.75 | Qualified | 0.93 |
Table 12 injection hydroxyl amylbenzene potassium formate (room temperature 12 months) and 0.9% sodium chloride compatibility stability
Table 13 injection hydroxyl amylbenzene potassium formate (room temperature 24 months) and 0.9% sodium chloride compatibility stability
Research confirms: even if under possible limiting case, after injection hydroxyl amylbenzene formates and 0.9% sodium chloride injection compatibility, when in solution, the content of n butylphthalide reaches 1.0%, in solution, particulate matter meets States Pharmacopoeia specifications clinical application standard, illustrates that the application of its clinical compatibility is safe.
5, irritate, haemolysis, sensitivity test
Get and adopt prescription 13 and above-mentioned method for making, obtained injection hydroxyl amylbenzene potassium formate sample, carry out irritating, haemolysis, sensitivity test, investigate the drug safety of medicine.
(1) rabbit injects blood vessel and the muscle irritation test of hydroxyl amylbenzene potassium formate
Nomenclature of drug: injection hydroxyl amylbenzene potassium formate, white lyophilized powder, soluble in water.
Laboratory animal: Japan large ear rabbit, male 12, about 2.5kg.
According to the principle that drug administration by injection position irritation test should be identical with clinical administration concentration, hydroxyl amylbenzene potassium formate clinical vein instillation Drug level is 1mgml
-1or 2mgml
-1, therefore this Setup Experiments hydroxyl amylbenzene potassium formate concentration is 1mgml
-1, 2mgml
-1.
12 rabbit are divided into two groups at random, often organize 6.This experiment adopts consubstantiality left and right sides self-controlled method, all left side injection test medicine, right side injecting normal saline.
Route of administration: auricular vein and quadriceps femoris drug administration by injection.
Administration volume: intravenous injection 0.8mlkg
-1, intramuscular injection 0.2mlkg
-1.
Administration time: every day 1 time (8:30 ~ 10:00 in the morning).
The administration time limit: successive administration 7 days.
Test sample is prepared: take a certain amount of injection hydroxyl amylbenzene potassium formate, add appropriate normal saline and make it dissolve completely, and after standardize solution, mixing uses, and faces with now joining.Medicinal liquid pH value: medicinal liquid pH value about 12.0 before lyophilizing, adds medicinal liquid pH value 10 ~ 11 after normal saline dilution.
Result judges and evaluates
Vascular stimulation tests
Vascular stimulation evaluation of result is undertaken by table 14 and table 15.
Table 14 vascular stimulation reaction perusal grade scale
Table 15 vascular stimulation reaction histopathology standard
Muscle irritation is tested
Muscular irritation result carries out classification by table 16, and order of reaction sum is less than 10, then think that test sample is muscular irritation agreement with experimental regulation, when being greater than 2 with each peak of quadriceps femoris order of reaction of group and the difference of minimum, should separately getting rabbit and again testing.
Table 16 muscular irritation reaction grade scale
| Irritant reaction | Classification |
| Without significant change | 0 |
| Mild hyperaemia, or scope is at 0.5 × below 1.0cm | 1 |
| Moderate is congested, or scope is at 0.5 × more than 1.0cm | 2 |
| Severe is congested, with myodegeneration | 3 |
| Occur downright bad, have brown degeneration | 4 |
| Occur that popularity is downright bad | 5 |
Result and discussion
Animal ordinary circumstance
In process of the test, hydroxyl amylbenzene potassium formate 2mgkg
-1organize 1 animal dead after diarrhoea appears in experiment the 8th day, this animal experiment in 1st ~ 7 days normal, the body weight of general state increase to some extent, Non Apparent Abnormality symptom before dead; All the other 11 animals show no obvious abnormalities performance.
Ordinary circumstance according to animal each in this test shows, and in conjunction with existing hydroxyl amylbenzene potassium formate toxicity test data, comprehensively analyzes, and can confirm caused by animal non-drug toxicity dead in this test.
Local excitation reaction visual results
Perusal in process of the test, injection hydroxyl amylbenzene potassium formate 1mgml
-16 animals and 2mgml
-16 animals on the left of auricular vein blood vessel have no hyperemia, edema, ulcer and the local excitation such as hemorrhage and sexually revise, on the right side of the control sides of each animal injecting normal saline auricular vein blood vessel also no abnormality seen change.
Injection hydroxyl amylbenzene potassium formate 1mgml
-16 animals and 2mgml
-16 animal left quadriceps local without changes such as congested, downright bad and cirrhosis, the right quadriceps femoris of control sides of each animal injecting normal saline also no abnormality seen changes.
Pathological examination results
Hydroxyl amylbenzene potassium formate 1mgkg
-1group and 2mgkg
-1the muscular irritation reaction scoring organizing each animals administer side and control sides is 1 point, and order of reaction sum is 6, and the difference of peak and minimum is 0.
According to above pathological examination results, can think that comparing hydroxyl amylbenzene potassium formate administration group with matched group has no stimulation to blood vessel and muscle.
Conclusion: under this experiment condition, rabbit vein injection or intramuscular injection concentration are respectively 1mgml
-1and 2mgml
-1hydroxyl amylbenzene potassium formate time, injection hydroxyl amylbenzene potassium formate side local vascular and muscle have no obvious stimulation reaction.The result shows, hydroxyl amylbenzene potassium formate is 1mgml in concentration
-1and 2mgml
-1time intravenous injection or intramuscular injection injection site is had no stimulation.
(2) hydroxyl amylbenzene potassium formate hemolysis in vitro test
Can object: observe hydroxyl amylbenzene potassium formate and cause rabbit erythrocyte hemolysis under in vitro conditions, could provide basis for estimation by injection for intravenous for evaluating hydroxyl amylbenzene potassium formate.
Method: concentration is respectively 1mgml
-1and 2mgml
-1hydroxyl amylbenzene potassium formate and the 2% rabbit erythrocyte suspension of different volumes hatch 3 hours jointly, establish negative control group and positive controls simultaneously, detect absorbance and blood counting instrument detection RBC number by perusal, spectrophotometer, judge whether tested material exists hemolytic.
Result: in experimentation, perusal shows, and is added with 1mgml
-1and 2mgml
-1the test tube of hydroxyl amylbenzene potassium formate and the solution of negative control group test tube are all the time in clear; Positive controls test tube solution becomes transparent redness gradually from hatching 15min ~ 45min, and continues to experiment end; In experiment, all test tubes are showed no and produce red floccule.Spectrophotometer method is shown in 1mgml
-1and 2mgml
-11 ~ No. 5 test tube hemolysis rate of hydroxyl amylbenzene potassium formate is all less than 5, and the hemolysis rate of 6, No. 7 test tubes is less than 1%, and the hemolysis rate of 8, No. 9 test tubes is all greater than 96%.Red cell preservation rate in erythrocyte in vitro counting method, 1mgml
-1and 2mgml
-11 ~ No. 5 test tube of hydroxyl amylbenzene potassium formate is all more than or equal to 77%, and 6, No. 7 test tubes are all greater than 82%, and 8, No. 9 test tubes are all less than 66%.
Conclusion: under this experiment condition, concentration is 1mgml
-1and 2mgml
-1after the hydroxyl amylbenzene potassium formate medicinal liquid of different volumes and 2% rabbit erythrocyte suspension hatch 3 hours jointly, haemolysis does not occur, therefore prompting hydroxyl amylbenzene potassium formate do not have haemolysis under in vitro conditions.
(3) whole body of hydroxyl amylbenzene potassium formate initiatively hypersensitive test
Object: after observing Cavia porcellus intravenous injection hydroxyl amylbenzene potassium formate, whether I type anaphylaxis can occur.
Method: experiment selects 24 Hartley Cavia porcelluss, male and female half and half.If negative control group, hydroxyl amylbenzene potassium formate small dose group 3mgkg
-1, hydroxyl amylbenzene potassium formate heavy dose group 30mgkg
-1(being equivalent to 1.3 times and 13.3 times of rat effective dose by body surface area conversion respectively), positive controls.Adopt whole body initiatively hypersensitive test, within 14 days, carry out exciting observing after 5 sensitization, last sensitization.
Result: low dose of, the heavy dose of group of negative control group and hydroxyl amylbenzene potassium formate has no symptoms of allergic to observing end after excitation at once, all animals of positive controls are dead in 3min all after excitation.The anaphylaxis of prompting hydroxyl amylbenzene potassium formate experimental group is negative.
Conclusion: in sum, under this experiment condition, Cavia porcellus intravenous injection hydroxyl amylbenzene potassium formate is not observed animal through predisposing medical conditions experiment and is occurred I type anaphylaxis.
Get the same method of hydroxyl amylbenzene formic acid sodium salt to investigate, obtain identical stability result.
Embodiment 11
The present invention has investigated the steadiness of hydroxyl amylbenzene formates in pH value 8.0 ~ 9.5 solution, and method is as follows:
Get hydroxyl amylbenzene potassium formate appropriate, respectively with the buffer solution that pH value is between 8.0 ~ 9.5, standardize solution.Place in 60 DEG C of constant temperature, get solution to be measured appropriate at interval of 2h, add mobile phase and make the solution containing hydroxyl amylbenzene potassium formate 0.5mg in 1ml, as need testing solution, the chromatographic condition empirically under example 1 measures.Get need testing solution sample introduction 10 μ L, record chromatogram, area normalization method calculates the content of n butylphthalide, the variation tendency of major impurity under investigation condition of different pH.
The results are shown in Table 17.
Hydroxyl amylbenzene potassium formate study on the stability result under the condition of table 17pH8.0 ~ 9.5
Table 17 is visible, the stability of hydroxyl amylbenzene potassium formate in the aqueous solution of pH8.0 ~ 9.5 comparatively acid condition is slightly good, but between pH value 9.0 ~ 9.5, have no obvious difference, suitable pH value still cannot be found to ensure to obtain stable hydroxyl amylbenzene formates injection or freeze-dried powder.
Embodiment 12
The present invention has investigated the control situation of solution ph 9.6 ~ 13.0 alkaline solution to major impurity in hydroxyl amylbenzene formates, and method is as follows:
Get hydroxyl amylbenzene potassium formate appropriate, respectively with the buffer solution that pH value is between 9.6 ~ 13.0, standardize solution.Place in 60 DEG C of constant temperature, get solution to be measured appropriate at interval of 2h, add mobile phase and make the solution containing hydroxyl amylbenzene potassium formate 0.5mg in 1ml, as need testing solution, the chromatographic condition empirically under example 1 measures.Get need testing solution sample introduction 10 μ L, record chromatogram, area normalization method calculates the content of n butylphthalide, the control situation of major impurity under investigation alkali condition.
The results are shown in Table 18.
Table 18
From table 18, be that the degradation speed of hydroxyl amylbenzene potassium formate in the solution of 9.6 ~ 13.0 is comparatively slow at pH value, particularly solution ph is more than 10.0, and principal degradation impurity n butylphthalide can control in lower level.
Get the same method of hydroxyl amylbenzene formic acid sodium salt to investigate, obtain identical stability result.
Claims (10)
1. a freeze-drying preparation for injection for hydroxyl amylbenzene formates, said preparation comprises:
A), 2-(Alpha-hydroxy amyl group) benzoate; With
B), adjuvant; Wherein adjuvant comprises excipient, pH value regulator.
2. a freeze-drying preparation for injection for hydroxyl amylbenzene formates, said preparation comprises:
A), 2-(Alpha-hydroxy amyl group) benzoate; With
B), adjuvant; Wherein adjuvant comprises excipient, pH value regulator, and pH value regulator consumption in order to the pH value range comprising the solution of water, adjuvant and hydroxyl amylbenzene formates before making lyophilizing is: 10.0 ~ 13.0.
3. preparation as claimed in claim 1 or 2, wherein, 2-(Alpha-hydroxy amyl group) salt of benzoate be selected from potassium salt, sodium salt, lithium salts or calcium salt, magnesium salt, zinc salt one or more.
4. preparation as claimed in claim 3, wherein, the consumption weight ratio of adjuvant and hydroxyl amylbenzene formates is 0.1 ~ 20:1.
5. preparation as claimed in claim 3, wherein, pH value regulator consumption is 11.0 ~ 12.5 in order to include the pH value range of the solution of water, adjuvant and hydroxyl amylbenzene formates before making lyophilizing.
6. preparation as claimed in claim 3, wherein, pH adjusting agent be selected from organic acid, mineral acid, organic base, inorganic base, buffer agent one or more.
7. preparation as claimed in claim 3, wherein, excipient be selected from sodium chloride, mannitol, sorbitol, dextran, lactose, sucrose, glucose and lactose one or more.
8. 2-(Alpha-hydroxy amyl group) preparation method of freeze-drying preparation for injection of benzoate, the method comprises:
1) choose raw material, raw material comprises gets hydroxyl amylbenzene formates, adjuvant, water; Wherein, adjuvant comprises pH adjusting agent, excipient;
2) adjuvant is dissolved in the water is formed after solution, then add hydroxyl amylbenzene formates in this solution; Wherein control hydroxyl amylbenzene formates and add pH value range 10.5 ~ 13.0 that is fashionable and solution after adding; With
3) lyophilizing.
9. method as claimed in claim 8, wherein, control hydroxyl amylbenzene formates add fashionable and after adding the pH value range of solution be 11.0 ~ 12.5.
10. the preparation method of preparation as described in any one of claim 1-7, the method comprises:
1) choose raw material, raw material comprises gets hydroxyl amylbenzene formates, adjuvant, water; Wherein, adjuvant comprises pH adjusting agent, excipient;
2) adjuvant is dissolved in the water is formed after solution, then add hydroxyl amylbenzene formates in this solution; Wherein control hydroxyl amylbenzene formates and add pH value range 10.5 ~ 13.0 that is fashionable and solution after adding; With
3) lyophilizing.
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|---|---|---|---|
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|---|---|---|---|
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1382682A (en) * | 2002-05-09 | 2002-12-04 | 中国医学科学院药物研究所 | 2-(alpha-hydroxypentyl) benzoate and its preparing process and usage |
| CN103142513A (en) * | 2013-03-25 | 2013-06-12 | 石家庄鸯星科技有限公司 | Racemized 2-(alpha-hydroxypentyl) benzoate freeze-dried powder needle for injection, and preparation method thereof |
-
2013
- 2013-08-28 CN CN201310382834.9A patent/CN104414981A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1382682A (en) * | 2002-05-09 | 2002-12-04 | 中国医学科学院药物研究所 | 2-(alpha-hydroxypentyl) benzoate and its preparing process and usage |
| US20090227809A1 (en) * | 2002-05-09 | 2009-09-10 | The Institute Of Materia Medica Of Chinese Academy Of Medical Sciences. | New 2-(alpha-hydroxypentyl) benzoates, their preparations and their uses |
| CN103142513A (en) * | 2013-03-25 | 2013-06-12 | 石家庄鸯星科技有限公司 | Racemized 2-(alpha-hydroxypentyl) benzoate freeze-dried powder needle for injection, and preparation method thereof |
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| Title |
|---|
| 李江，等: "2－(α－羟基戊基)苯甲酸钾冻干粉注射液的血管及肌肉刺激、溶血、过敏试验研究", 《中国药业》 * |
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