CN103142513B - A kind of injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof - Google Patents
A kind of injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof Download PDFInfo
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- CN103142513B CN103142513B CN201310097200.9A CN201310097200A CN103142513B CN 103142513 B CN103142513 B CN 103142513B CN 201310097200 A CN201310097200 A CN 201310097200A CN 103142513 B CN103142513 B CN 103142513B
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- 230000006340 racemization Effects 0.000 title claims abstract description 46
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 239000000843 powder Substances 0.000 title claims abstract description 18
- 238000002347 injection Methods 0.000 title claims abstract description 16
- 239000007924 injection Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 39
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 239000002671 adjuvant Substances 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 7
- 239000012467 final product Substances 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 239000008215 water for injection Substances 0.000 claims description 5
- 239000012530 fluid Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 238000004806 packaging method and process Methods 0.000 claims description 4
- 238000007789 sealing Methods 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- 239000004411 aluminium Substances 0.000 claims description 3
- 239000012528 membrane Substances 0.000 claims description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 3
- 235000010234 sodium benzoate Nutrition 0.000 claims description 3
- 239000004299 sodium benzoate Substances 0.000 claims description 3
- 229920005549 butyl rubber Polymers 0.000 claims description 2
- 238000005516 engineering process Methods 0.000 abstract description 8
- 239000003513 alkali Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 229940050390 benzoate Drugs 0.000 description 24
- HJXMNVQARNZTEE-UHFFFAOYSA-N Butylphthalide Chemical compound C1=CC=C2C(CCCC)OC(=O)C2=C1 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 description 20
- 229950005197 butylphthalide Drugs 0.000 description 10
- 239000000203 mixture Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- 235000010235 potassium benzoate Nutrition 0.000 description 3
- 239000004300 potassium benzoate Substances 0.000 description 3
- 229940103091 potassium benzoate Drugs 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 241000700159 Rattus Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- -1 anilino- Chemical group 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical group CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical group [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000011575 calcium Chemical group 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Chemical group 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Chemical group 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention is injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof, injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder comprises following component: racemization 2-(Alpha-hydroxy amyl group) benzoate 5% ~ 95%, pin adjuvant 5% ~ 95%, above each component by weight.The alkalization preparation technology of pharmaceutically acceptable alkali adjust ph to 11.0 ~ 13.0 is adopted in preparation method, solve active component racemization 2-(Alpha-hydroxy amyl group) benzoate easily to degrade in preparation technology at lyophilized preparation, the problem of poor stability, the principal agent stability of injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder can be made obviously to increase, be applicable to the preparation of this medicine freeze-dried powder.
Description
Technical field
The present invention relates to a kind of racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof, belong to medical art.
Background technology
Racemization 2-(Alpha-hydroxy amyl group) benzoate is the prodrug of racemization butylphthalide, can be converted into racemization butylphthalide fast and play drug effect in vivo.After dog and rat intravenous injection racemization 2-(Alpha-hydroxy amyl group) benzoate, it fast, fully can be converted into racemization butylphthalide in vivo, in blood plasma, racemization butylphthalide exposure value and the exposure value ratio of direct quiet note racemization butylphthalide, be respectively 97.4 (rats) and 112.5% (dog).Illustrate that racemization 2-(Alpha-hydroxy amyl group) benzoate enters after in body, can be converted into racemization butylphthalide fast and fully, its pharmacokinetic parameter and direct quiet note racemization butylphthalide are closely.In addition, pharmacodynamic study shows, racemization 2-(Alpha-hydroxy amyl group) benzoate has the biological effect similar or stronger to racemization butylphthalide.
Racemization 2-(Alpha-hydroxy amyl group) benzoate and method for making thereof and purposes is disclosed in the patent CN01109795.7 of institute of Materia Medica,Chinese Academy of Medical Sciences application, and refer to about racemization 2-(Alpha-hydroxy amyl group) benzoate, tablet, capsule, injection or lyophilized preparation etc. can be made, and disclose a kind of formula and preparation method of lyophilized preparation in an embodiment, but unexposed detailed preparation method.
Due to the less stable of racemization 2-(Alpha-hydroxy amyl group) benzoate in neutrality and acidic aqueous solution, in the lyophilized preparation preparation technology of routine, or formula and preparation method disclosed in application patent CN01109795.7, easily degrade, poor stability.Therefore, a series of groping is carried out for the preparation technology of racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder.
Summary of the invention
The present invention easily degrades in the preparation technology of conventional lyophilized preparation to solve active component racemization 2-(Alpha-hydroxy amyl group) benzoate, the problem of poor stability, provides a kind of racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof.Racemization 2-(Alpha-hydroxy amyl group) benzoate is the compound containing general formula I, and wherein general formula I is: n=1 or 2, M is potassium, sodium, lithium, calcium, magnesium, zinc ion or anilino-, benzyl amino, morpholinyl and diethylin.
Racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof comprises following processing step:
A) preparation of injection pharmaceutically acceptable auxiliaries solution: take injection pharmaceutically acceptable auxiliaries, adds 70% ~ 80% water for injection, is stirred to dissolve, with pharmaceutically acceptable alkali adjust ph to 11.0 ~ 13.0;
B) take racemization 2-(Alpha-hydroxy amyl group) benzoate of regulation, be dissolved in above-mentioned pin adjuvant solution, mixing;
C) prescribed volume is added water for injection to, and with pharmaceutically acceptable alkali adjust ph to 11.0 ~ 13.0;
D) aseptic filtration, fill;
E) lyophilizing.
Injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder, comprises following component: racemization 2-(Alpha-hydroxy amyl group) benzoate 5% ~ 95%, and pin adjuvant 5% ~ 95%, above each component by weight.
One or more in the optional low molecular dextran of pin adjuvant, cyclodextrin, soluble starch, sodium chloride, inositol, sorbitol, benzoic acid or cellulose substances.
In preparation method, the pharmaceutically acceptable alkali of adjust ph to 11.0 ~ 13.0 is sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydrogen phosphate etc., or more two or more mixture.
In preparation method, processing step d) aseptic filtration, fill: by aseptic manipulation requirement, terminal crosses the microporous filter membrane of 0.22 μM, considers degerming, and fill is in the ampoule bottle or cillin bottle of sterilizing.
In preparation method, processing step e) lyophilizing: by the medicinal liquid after fill, carry out pre-freeze in-30 DEG C ~-50 DEG C, when fluid temperature reaches within the scope of-30 DEG C ~-50 DEG C, insulation a few hours; Being warming up within the scope of-35 DEG C ~ 0 DEG C, carry out sublimation drying, through one or many intensification, insulating process, to 0 DEG C; Again through one or many heat up, insulating process to 20 DEG C ~ 50 DEG C, insulation a few hours, getting final product outlet, as carried out lyophilizing with cillin bottle subpackage, can seal, packaging, to obtain final product.
Advantage of the present invention: compare with preparation method with formula disclosed in patent CN01109795.7, in preparation technology, apply pH value to 11.0 ~ 13.0 that pharmaceutically acceptable alkali regulates fill solution, efficiently solve racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder at the stability problem prepared and deposit in process.
The quality determining method of injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder:
Racemization 2-(Alpha-hydroxy amyl group) benzoate content assaying method: get this product 1, adds mobile phase and makes dissolving in right amount and be diluted in 100ml volumetric flask with mobile phase, filters, obtains need testing solution; Another precision takes principal agent reference substance 10mg in 20ml volumetric flask, adds mobile phase and makes dissolving in right amount and be diluted to scale with mobile phase, shake up, and filters, obtains reference substance solution.Get need testing solution and each 10 μ L of reference substance solution injection liquid chromatography respectively, record chromatogram, by external standard method with calculated by peak area, to obtain final product.
Formula and preparation method disclosed in application patent CN01109795.7, embodiment 17 is set to reference examples, and concrete prescription is in table 1.
Preparation method: principal agent is dissolved in water for injection, regulates pH8.5 ~ 9.5 with sodium hydrate aqueous solution, and filter, lyophilizing: by the medicinal liquid after fill, carries out pre-freeze in-35 DEG C, when fluid temperature reaches-35 DEG C, maintains 4 hours; Be warming up to-30 DEG C at 4 hours, maintain 20 hours, vacuum < 20Pa; Again be warmed up to-10 DEG C at 6 hours, maintain 3 hours, within 2 hours, be warmed up to 0 DEG C, within 2 hours, be warmed up to 30 DEG C, maintain a few hours dry, tamponade, the sealing of lock aluminium lid, packaging, to obtain final product.
Table 1. reference examples: 500 (specification: 100mg/ props up)
| Principal agent | 50g |
| Sodium hydroxide | (regulate pH9.5) in right amount |
Result shows: adopt formula and preparation method disclosed in patent CN01109795.7, lyophilizing in cillin bottle, places measure related substance situation of change in 30 days in constant temperature (45 DEG C).After measured, the content of racemization butylphthalide obviously increases result, and more than 20%, and drug content obviously reduces, and other impurity increases not obvious.Therefore, formula disclosed in patent CN01109795.7 and preparation method are not suitable for the preparation of injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder.
Find in prescription screening process:
The less stable of principal agent in neutrality or acidic aqueous solution, main manifestations is that drug content obviously declines, cyclization catabolite racemization butylphthalide obviously increases, and clarity is deteriorated.And when pH value is 11.0 ~ 13.0, drug content is stablized, be applicable to the preparation of lyophilized preparation.
Cancellation is revolved 2-(Alpha-hydroxy amyl group) Potassium Benzoate and is about 20mg, puts in 50ml measuring bottle, adds the 0.1M phosphate buffer that pH value is 4.0,6.0,8.0,9.0,10.0,11.0,12.0 and 13.0 respectively, dissolve, standardize solution, sealing, obtains need testing solution.Place 24h in 60 DEG C of constant temperature, get need testing solution 10 μ L injection liquid chromatography respectively, record chromatogram, investigates the situation of change of different time peak area.Measured main peak area for 100% with 0 hour, calculate the percentage contents of each time point after placing, the results are shown in Table 2.
The relative amount of table 2. racemization 2-(Alpha-hydroxy amyl group) Potassium Benzoate under condition of different pH investigates result (60 DEG C, 24h)
Basification technique is adopted: after supplementary material alkalization (pH11.0 ~ 13.0), then through fill, lyophilizing in preparation technology.The principal agent stability of racemization 2-(Alpha-hydroxy amyl group) benzoate can be made obviously to increase, thus solve the problem of principal agent in freeze-dried powder quality instability.
It has good moldability, instant, clear and bright, stable, accumulating and the feature such as easy to use.
Detailed description of the invention
The following examples can make the present invention of those skilled in the art comprehend, but do not limit the present invention in any way.
Embodiment 1.
Prescription composition (1000,25mg/ props up)
Racemization 2-(Alpha-hydroxy amyl group) sodium benzoate 25g
Sodium chloride 15g
Disodium hydrogen phosphate,anhydrous 3g
Preparation method: adjuvant is dissolved in water for injection, by sodium hydrate aqueous solution adjust ph to 12.0 after dissolving; Principal agent is added the adjuvant solubilize that above-mentioned pH value is 12.0, inject with water, and regulate solution ph to 12.0 with sodium hydroxide solution, final volume 1000mL; Cross 0.22 μm of microporous filter membrane degerming; Fill, 1ml/ props up; Partly press butyl rubber plug, put in freeze dryer and carry out lyophilizing: by the medicinal liquid after fill, carry out pre-freeze in-35 DEG C, when fluid temperature reaches-35 DEG C, maintain 4 hours; Be warming up to-30 DEG C at 4 hours, maintain 20 hours, vacuum < 20Pa; Again be warmed up to-10 DEG C at 6 hours, maintain 3 hours, within 2 hours, be warmed up to 0 DEG C, within 2 hours, be warmed up to 30 DEG C, maintain a few hours dry, and control moisture < 2%, tamponade, the sealing of lock aluminium lid, packaging, to obtain final product.
Embodiment 2.
Prescription composition (1000,25mg/ props up)
Racemization 2-(Alpha-hydroxy amyl group) sodium benzoate 25g
Sodium chloride 90g
Disodium hydrogen phosphate,anhydrous 5g
Preparation method: with embodiment 1.
Embodiment 3.
Prescription composition (1000,25mg/ props up)
Racemization 2-(Alpha-hydroxy amyl group) Potassium Benzoate 25g
Sodium chloride 90g
Disodium hydrogen phosphate,anhydrous 6g
Preparation method: with example 1.
Embodiment 4.
Prescription composition (1000,25mg/ props up)
Preparation method: with embodiment 1.
Embodiment 5. is investigated above-described embodiment dried frozen aquatic products room temperature and is preserved the outward appearance after 12 months and solubility
After above-described embodiment dried frozen aquatic products room temperature (25 ± 2 DEG C) is preserved 12 months, observe the solubility of outward appearance and the 5mL that adds water, the results are shown in Table 3.
The outward appearance of table 3 injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder and solubility
| Inspection item | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 |
| Outward appearance | Not full | Full, solid | Full, solid | Full, solid |
| Solubility (5) | Jog is instant | Jog is instant | Jog is instant | Jog is instant |
Embodiment 6. investigates the principal agent quality stability of above-described embodiment
Above-described embodiment dried frozen aquatic products room temperature (25 ± 2 DEG C) is carried out long-time stability investigation, leading indicator and the results are shown in Table 4.
Table 4 injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder embodiment study on the stability result
Claims (1)
1. injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder, it is characterized in that, with 1000,25mg/ props up meter, and prescription is composed as follows:
Racemization 2-(Alpha-hydroxy amyl group) sodium benzoate 25g;
Sodium chloride 90g;
Disodium hydrogen phosphate,anhydrous 5g;
It obtains by the following method: adjuvant is dissolved in water for injection, by sodium hydrate aqueous solution adjust ph to 12.0 after dissolving; Principal agent is added the adjuvant solubilize that above-mentioned pH value is 12.0, inject with water, and regulate solution ph to 12.0 with sodium hydroxide solution, final volume 1000mL; Cross 0.22 μm of microporous filter membrane degerming; Fill, 1ml/ props up; Partly press butyl rubber plug, put in freeze dryer and carry out lyophilizing: by the medicinal liquid after fill, carry out pre-freeze in-35 DEG C, when fluid temperature reaches-35 DEG C, maintain 4 hours; Be warming up to-30 DEG C at 4 hours, maintain 20 hours, vacuum < 20Pa; Again be warmed up to-10 DEG C at 6 hours, maintain 3 hours, within 2 hours, be warmed up to 0 DEG C, within 2 hours, be warmed up to 30 DEG C, maintain a few hours dry, and control moisture < 2%, tamponade, the sealing of lock aluminium lid, packaging, to obtain final product.
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| CN201310097200.9A CN103142513B (en) | 2013-03-25 | 2013-03-25 | A kind of injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof |
| CN201510695852.1A CN105343014B (en) | 2013-03-25 | 2013-03-25 | Injection racemization 2- (Alpha-hydroxy amyl) benzoate freeze-dried powder and preparation method thereof |
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| CN201310097200.9A CN103142513B (en) | 2013-03-25 | 2013-03-25 | A kind of injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof |
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|---|---|---|---|---|
| CN104415020A (en) * | 2013-08-28 | 2015-03-18 | 云南昊邦制药有限公司 | Hydroxypentyl benzoate injection and preparation method thereof |
| CN104414981A (en) * | 2013-08-28 | 2015-03-18 | 云南昊邦制药有限公司 | Freeze-dried hydroxyl-pentyl benzoate preparation for injection and preparation method of freeze-dried hydroxyl-pentyl benzoate preparation for injection |
| CN108703953A (en) * | 2018-08-27 | 2018-10-26 | 海南皇隆制药股份有限公司 | A kind of injection benzene sulphur is along atracurium freeze drying powder injection and preparation method thereof |
Citations (5)
| 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 |
| CN1523003A (en) * | 2003-09-01 | 2004-08-25 | 北京天衡药物研究院 | Novel 2-(alpha-hydroxyl amyl) and its preparing method and use |
| CN1594270A (en) * | 2004-06-17 | 2005-03-16 | 北京天衡药物研究院 | Novel L-2-(alpha-hydroxy pentyl)benzoate and its preparation method and use |
| CN101054346A (en) * | 2006-04-13 | 2007-10-17 | 温建波 | Preparation method and use for a set of novel compound and composition thereof |
| CN101627984A (en) * | 2008-07-14 | 2010-01-20 | 中国医学科学院药物研究所 | Application of 2-(alpha- hydroxyl amyl) potassium benzoate in preventing and/or treating senile dementia |
-
2013
- 2013-03-25 CN CN201510695852.1A patent/CN105343014B/en active Active
- 2013-03-25 CN CN201310097200.9A patent/CN103142513B/en active Active
Patent Citations (5)
| 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 |
| CN1523003A (en) * | 2003-09-01 | 2004-08-25 | 北京天衡药物研究院 | Novel 2-(alpha-hydroxyl amyl) and its preparing method and use |
| CN1594270A (en) * | 2004-06-17 | 2005-03-16 | 北京天衡药物研究院 | Novel L-2-(alpha-hydroxy pentyl)benzoate and its preparation method and use |
| CN101054346A (en) * | 2006-04-13 | 2007-10-17 | 温建波 | Preparation method and use for a set of novel compound and composition thereof |
| CN101627984A (en) * | 2008-07-14 | 2010-01-20 | 中国医学科学院药物研究所 | Application of 2-(alpha- hydroxyl amyl) potassium benzoate in preventing and/or treating senile dementia |
Also Published As
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|---|---|
| CN105343014B (en) | 2018-08-24 |
| CN105343014A (en) | 2016-02-24 |
| CN103142513A (en) | 2013-06-12 |
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