CN103142513A - Racemized 2-(alpha-hydroxypentyl) benzoate freeze-dried powder needle for injection, and preparation method thereof - Google Patents
Racemized 2-(alpha-hydroxypentyl) benzoate freeze-dried powder needle for injection, and preparation method thereof Download PDFInfo
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- CN103142513A CN103142513A CN2013100972009A CN201310097200A CN103142513A CN 103142513 A CN103142513 A CN 103142513A CN 2013100972009 A CN2013100972009 A CN 2013100972009A CN 201310097200 A CN201310097200 A CN 201310097200A CN 103142513 A CN103142513 A CN 103142513A
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- benzoate
- alpha
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- freeze
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- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000002347 injection Methods 0.000 title claims abstract description 24
- 239000007924 injection Substances 0.000 title claims abstract description 24
- 239000000843 powder Substances 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 12
- 230000001105 regulatory effect Effects 0.000 claims abstract description 3
- 230000006340 racemization Effects 0.000 claims description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000002671 adjuvant Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 239000012467 final product Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 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
- 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 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- -1 anilino- Chemical class 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 238000012856 packing Methods 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000012545 processing Methods 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- 239000008215 water for injection Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 238000009413 insulation Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- 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 claims description 2
- 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 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 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 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 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 claims description 2
- 229960000367 inositol Drugs 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 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 claims description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 238000000859 sublimation Methods 0.000 claims description 2
- 230000008022 sublimation Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract 1
- 239000004615 ingredient Substances 0.000 abstract 1
- 230000021962 pH elevation Effects 0.000 abstract 1
- 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
- 238000005516 engineering process Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 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
- 239000013558 reference substance Substances 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 241000700159 Rattus Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 239000003708 ampul Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229920005549 butyl rubber Polymers 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000012535 impurity Substances 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
- 230000007935 neutral effect Effects 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
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 238000004321 preservation Methods 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
- 238000012216 screening Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a racemized 2-(alpha-hydroxypentyl) benzoate freeze-dried powder needle for injection, and a preparation method thereof. The racemized 2-(alpha-hydroxypentyl) benzoate freeze-dried powder for injection comprises the following ingredients in percentage by weight: 5-95% of racemized 2-(alpha-hydroxypentyl) benzoate and 5-95% of needle auxiliaries. According to the preparation method, the problems that the active ingredient racemized 2-(alpha-hydroxypentyl) benzoate is easily degraded and poor in stability in the preparation technique of the freeze-dried agent can be solved by adopting the alkalinization preparation technique capable of regulating the pH value to be 11.0-13.0 with officinal alkaline, the stability of main drugs in the injective racemized 2-(alpha-hydroxypentyl) benzoate freeze-dried powder needle can be obviously increased, thereby being applicable to preparation of the racemized 2-(alpha-hydroxypentyl) benzoate freeze-dried powder needle.
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 technical field.
Background technology
Racemization 2-(Alpha-hydroxy amyl group) benzoate is the prodrug of racemization butylphthalide, can be converted into fast the racemization butylphthalide in vivo and bring into play drug effect.After dog and rat intravenous injection racemization 2-(Alpha-hydroxy amyl group) benzoate, it can fast, fully be converted into the racemization butylphthalide in vivo, in blood plasma, the exposure value ratio of racemization butylphthalide exposure value and direct quiet notes racemization butylphthalide, be respectively 97.4 (rats) and 112.5% (dog).After illustrating that racemization 2-(Alpha-hydroxy amyl group) benzoate enters in body, can be fast and fully be converted into the racemization butylphthalide, its pharmacokinetic parameter and direct quiet notes racemization butylphthalide very approaching.In addition, pharmacodynamic study shows, racemization 2-(Alpha-hydroxy amyl group) benzoate has the biological effect similar or stronger to the racemization butylphthalide.
Disclose racemization 2-(Alpha-hydroxy amyl group) benzoate and method for making and purposes in the patent CN01109795.7 of institute of Materia Medica,Chinese Academy of Medical Sciences application, and mentioned the benzoate about racemization 2-(Alpha-hydroxy amyl group), can make tablet, capsule, injection or lyophilized preparation etc., and disclose in an embodiment a kind of formula and preparation method of lyophilized preparation, but unexposed detailed preparation method.
Due to the less stable of racemization 2-(Alpha-hydroxy amyl group) benzoate in neutral and acidic aqueous solution, in the lyophilized preparation preparation technology of routine, or use disclosed formula and preparation method in patent CN01109795.7, and easily degrade, poor stability.Therefore, the preparation technology for racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder has carried out a series of groping.
Summary of the invention
The present invention easily degrades in the preparation technology of conventional lyophilized preparation in order 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 that contains general formula I, and wherein general formula I is: n=1 or 2, M are 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 the injection pharmaceutically acceptable auxiliaries, add 70%～80% water for injection, be stirred to dissolve, regulate pH value to 11.0～13.0 with pharmaceutically acceptable alkali;
B) take racemization 2-(Alpha-hydroxy amyl group) benzoate of regulation, be dissolved in above-mentioned pin with in adjuvant solution, mixing;
C) the supplementary injection water is to prescribed volume, and regulates pH value to 11.0～13.0 with pharmaceutically acceptable alkali;
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 is by weight.
One or more in the pin optional low molecular dextran of adjuvant, cyclodextrin, soluble starch, sodium chloride, inositol, sorbitol, benzoic acid or cellulose substances.
In preparation method, the pharmaceutically acceptable alkali of regulating pH value to 11.0～13.0 is sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydrogen phosphate etc., or above two or more mixture.
In preparation method, processing step d) aseptic filtration, fill: by the aseptic manipulation requirement, terminal is crossed the microporous filter membrane of 0.22 μ M, considers degerming, and fill is in the ampoule bottle or cillin bottle of sterilization.
In preparation method, processing step e) lyophilizing: with the medicinal liquid after fill, carry out pre-freeze in-30 ℃～-50 ℃, in the time of in fluid temperature reaches-30 ℃～-50 ℃ scopes, insulation a few hours; Be warming up in-35 ℃～0 ℃ scope, carrying out sublimation drying, through one or many intensification, insulating process, to 0 ℃; Again through one or many heat up, insulating process to 20 ℃～50 ℃, insulation a few hours, get final product outlet, as carrying out lyophilizing with the cillin bottle packing, can seal, pack, and get final product.
Advantage of the present invention: compare with the disclosed formula of patent CN01109795.7 and preparation method, use pharmaceutically acceptable alkali and regulate the pH value to 11.0 of fill solution～13.0 in preparation technology, efficiently solve racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder in preparation and the stability problem in depositing 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 1 of this product, add mobile phase and make in right amount dissolving and be diluted in the 100ml volumetric flask with mobile phase, filter, namely get need testing solution; Another precision takes principal agent reference substance 10mg in the 20ml volumetric flask, adds mobile phase and makes in right amount dissolving and be diluted to scale with mobile phase, shakes up, and filters, and namely gets reference substance solution.Get each 10 μ L of need testing solution and reference substance solution injection liquid chromatography respectively, record chromatogram, press external standard method with calculated by peak area, and get final product.
Use disclosed formula and preparation method in patent CN01109795.7, embodiment 17 is made as reference examples, concrete prescription sees Table 1.
Preparation method: principal agent is dissolved in water for injection, regulates pH8.5～9.5 with sodium hydrate aqueous solution, filter, lyophilizing: with the medicinal liquid after fill, carry out pre-freeze in-35 ℃, when fluid temperature reaches-35 ℃, kept 4 hours; Be warming up to-30 ℃ at 4 hours, kept vacuum＜20Pa 20 hours; Again be warmed up to-10 ℃ at 6 hours, kept 3 hours, be warmed up to 0 ℃ in 2 hours, be warmed up to 30 ℃ in 2 hours, keep a few hours drying, tamponade, the sealing of lock aluminium lid, packing, and get 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 disclosed formula and preparation method in patent CN01109795.7, lyophilizing in cillin bottle is placed in constant temperature (45 ℃) and was measured the related substance situation of change in 30 days.Result after measured, the content of racemization butylphthalide obviously increases, more than 20%, and drug content obviously reduces, other impurity increases not obvious.Therefore, in patent CN01109795.7, disclosed formula and preparation method are not suitable for the preparation of injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder.
Find in the prescription screening process:
The less stable of principal agent in neutrality or acidic aqueous solution, main manifestations are that drug content obviously descends, cyclization catabolite racemization butylphthalide obviously increases, the clarity variation.And be 11.0～13.0 o'clock at pH value, drug content is stable, is applicable to the preparation of lyophilized preparation.
Cancel and to revolve approximately 20mg of 2-(Alpha-hydroxy amyl group) Potassium Benzoate, put in the 50ml measuring bottle, add respectively pH value and be 4.0,6.0,8.0,9.0,10.0,11.0,12.0 and 13.0 0.1M phosphate buffer, dissolving, standardize solution, sealing namely gets need testing solution.Place 24h in 60 ℃ of constant temperature, get need testing solution 10 μ L injection liquid chromatography respectively, record chromatogram, investigate the situation of change of different time peak area.Measure the main peak area as 100% take 0 hour, calculate the relative percentage composition of each time point after placing, the results are shown in Table 2.
The relative amount investigation result of table 2. racemization 2-(Alpha-hydroxy amyl group) Potassium Benzoate under condition of different pH (60 ℃, 24h)
Adopt basification technique in preparation technology: after supplementary material alkalization (pH11.0～13.0), then through fill, lyophilizing.The principal agent stability of racemization 2-(Alpha-hydroxy amyl group) benzoate is obviously increased, thereby solved principal agent in the unsettled problem of freeze-dried powder quality.It has good moldability, instant, clear and bright, stable, accumulating and the characteristics such as easy to use.
The specific embodiment
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 forms (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, regulates pH value to 12.0 with sodium hydrate aqueous solution after dissolving; It is the dissolving of 12.0 adjuvant solution that principal agent is added above-mentioned pH value, injects water, and with sodium hydroxide solution regulator solution pH value to 12.0, final volume 1000mL; Cross 0.22 μ m microporous filter membrane degerming; Fill, 1ml/ props up; Partly press butyl rubber plug, put and carry out lyophilizing in freeze dryer: with the medicinal liquid after fill, carry out pre-freeze in-35 ℃, when fluid temperature reaches-35 ℃, kept 4 hours; Be warming up to-30 ℃ at 4 hours, kept vacuum＜20Pa 20 hours; Again be warmed up to-10 ℃ at 6 hours, kept 3 hours, be warmed up to 0 ℃ in 2 hours, be warmed up to 30 ℃ in 2 hours, keep a few hours drying, and control moisture＜2%, tamponade, the sealing of lock aluminium lid, packing, and get final product.
Embodiment 2.
Prescription forms (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 forms (1000,25mg/ props up)
Racemization 2-(Alpha-hydroxy amyl group) Potassium Benzoate 25g
Sodium chloride 90g
Disodium hydrogen phosphate,anhydrous 6g
Preparation method: with embodiment 1.
Embodiment 4.
Prescription forms (1000,25mg/ props up)
Preparation method: with embodiment 1.
Embodiment 5. investigates outward appearance and the solubility of above-described embodiment dried frozen aquatic products room temperature preservation after 12 months
After above-described embodiment dried frozen aquatic products room temperature (25 ± 2 ℃) is preserved 12 months, observe outward appearance and the solubility that adds water 5mL, the results are shown in Table 3.
Outward appearance and the solubility of table 3 injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder
| 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 ℃) is carried out long-time stability investigate, 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 (5)
1. injection racemization 2-(Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof, it is characterized in that racemization 2-(Alpha-hydroxy amyl group) benzoate is the compound that contains general formula I, wherein in general formula I: n=1 or 2, M are potassium, sodium, lithium, calcium, magnesium, zinc ion or anilino-, benzyl amino, morpholinyl and diethylin;
Its preparation method comprises following processing step:
A) preparation of injection pharmaceutically acceptable auxiliaries solution: take the injection pharmaceutically acceptable auxiliaries, add 70%～80% water for injection, be stirred to dissolve, regulate pH value to 11.0～13.0 with pharmaceutically acceptable alkali;
B) take racemization 2-(Alpha-hydroxy amyl group) benzoate of regulation, be dissolved in above-mentioned pin with in adjuvant solution, mixing;
C) the supplementary injection water is to prescribed volume, and regulates pH value to 11.0～13.0 with pharmaceutically acceptable alkali;
D) aseptic filtration, fill;
E) lyophilizing.
2. injection racemization 2-according to claim 1 (Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof, it is characterized in that comprising racemization 2-(Alpha-hydroxy amyl group) benzoate 5%～95%, pin adjuvant 5%～95%, above each component by weight.
3. injection racemization 2-according to claim 1 (Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof is characterized in that one or more in the optional low molecular dextran of injection pharmaceutically acceptable auxiliaries, cyclodextrin, soluble starch, sodium chloride, inositol, sorbitol, benzoic acid or cellulose substances.
4. injection racemization 2-according to claim 1 (Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof, the pharmaceutically acceptable alkali that it is characterized in that in preparation method regulating pH value to 11.0～13.0 is sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydrogen phosphate etc., or above two or more mixture.
5. injection racemization 2-according to claim 1 (Alpha-hydroxy amyl group) benzoate freeze-dried powder and preparation method thereof, it is characterized in that step e) lyophilizing: with the medicinal liquid after fill, carry out pre-freeze in-30 ℃～-50 ℃, in the time of in fluid temperature reaches-30 ℃～-50 ℃ scopes, be incubated a few hours; Be warming up in-35 ℃～0 ℃ scope, carrying out sublimation drying, through one or many intensification, insulating process, to 0 ℃; Again through one or many heat up, insulating process to 20 ℃～50 ℃, insulation a few hours, get final product outlet, as carrying out lyophilizing with the cillin bottle packing, can seal, pack, and get final product.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
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| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105343014A (en) | 2016-02-24 |
| CN103142513B (en) | 2016-01-20 |
| CN105343014B (en) | 2018-08-24 |
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