CN107303270A - It is a kind of to stablize oxidation resistant (S)-Esomeprazole parenteral solution - Google Patents
It is a kind of to stablize oxidation resistant (S)-Esomeprazole parenteral solution Download PDFInfo
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Abstract
Stablize the pyrrolidine acetamide parenteral solution of 2 oxo of oxidation resistant (S) 4 hydroxyl 1 the invention discloses a kind of；Contain following supplementary material in per mL parenteral solutions：(S) 4 hydroxyl, 2 oxo 1 180 ~ 220mg of pyrrolidine acetamide, 0.01 ~ 0.1mg of natrium adetate, 4 ~ 5mg of methyl hydroxybenzoate, 10 ~ 16mg of meglumine, 1 ~ 2mg of vitamin C, 1 ~ 3mg of ethylenediamine tetra-acetic acid, 1 ~ 3mg of phenmethylol；The preparation method of parenteral solution includes specific sterilizing program.(S) 4 hydroxyl 2 oxo, 1 pyrrolidine acetamide parenteral solution prepared by the present invention is non-foaming, there is no decoction adhesion problems, product yield is high, and with good stability, it is difficult to be oxidized, product total impurities increase in sterilization process is less, can mitigate patient's injection pain sense, good patient compliance.
Description
Technical field
The invention belongs to pharmaceutical field, and in particular to a kind of to stablize oxidation resistant (S) -4- hydroxyl -2- OXo-1-pyrrolidines
Acetyl amine injection.
Background technology
Cereboactive drug is also known as cereboactive drug, is a kind of promotion study, the new medicine for central nervous system of enhancing memory.
Nootropics requires selection index system in cerebral cortex, with selection activation, protection and promotion damaged nerve cell functional rehabilitation
Feature.Different from other neurologic agents be a little their above-mentioned effect not by network or olfactory bulb, but directly
Act on cortex.Behavior is neither influenceed, also without calm excitation, therefore such medicine has caused the extensive concern of people and emerging
Interest, the demand to such medicine is also growing day by day.
Oxiracetam (oxiracetam, CAS No.：62613-82-5) chemical entitled 4- hydroxyls -2- OXo-1-pyrrolidines
Acetamide, is that (compound is disclosed in the anti anoxia class cereboactive drug that was synthesized first in 1974 of Italian ISFS.P.A companies
US4118396), it is ring GABOB derivatives, Phosphorylcholine and phosphatidyl ethanolamine can be promoted to synthesize, promotes brain metabolism, through blood brain
Barrier, has stimulation to specific nervous centralis road, can improve intelligence and memory, to cerebrovascular disease, brain trauma, brain
Knurl, intracranial infection, brain degenerative disease etc. also have preferable curative effect, and the drug toxicity is extremely low, no mutagenesis and carcinogenic work
With and genotoxicity.Giorgio et al. discloses the chemical constitution and preparation method of Oxiracetam in US4118396,
Chiodini et al. is disclosed in WO9306826A, and clinical effectiveness proves that the drug effect of the Oxiracetam of S configurations (left-handed) is better than R structures
Type (dextrorotation), Oxiracetam and levo-oxiracetam structure are as follows.
Easily there is foam in pouring process in existing (S)-Esomeprazole parenteral solution,
Filling using ampoule bottle, decoction will adhere to bottleneck, cause decoction carbonization to make product visible foreign matters during ampoule bottle heat sealing
It is unqualified, product yield is reduced, while also increasing the unknown security of patient medication；It is filling using cillin bottle, solution adhesion
To bottleneck, easily occur the situation of plug jumping, equally reduce product yield.In addition, existing (S) -4- hydroxyl -2- oxos -1-
Pyrrolidine acetamide parenteral solution also exist oxidizable, sterilization process easily cause impurity to increase, injection process pain substantially, Huan Zheshun
The problems such as answering property is poor.
The content of the invention
In view of this, oxidation resistant (S) -4- hydroxyls -2- oxo -1- pyrroles is stablized it is an object of the invention to provide a kind of
Alkyl acetamide parenteral solution, product stability is good, not oxidizable, sterilization process impurity increment is few, and decoction is non-foaming, viscous without decoction
Even problem, and patient's injection pain sense, good patient compliance can be mitigated.
To reach above-mentioned purpose, the present invention provides following technical scheme：
It is a kind of to stablize oxidation resistant (S)-Esomeprazole parenteral solution, contain in every mL parenteral solutions
There is following supplementary material：(S) -180~220mg of Esomeprazole, natrium adetate 0.01~
0.1mg, 4~5mg of methyl hydroxybenzoate, 10~16mg of meglumine, 1~2mg of vitamin C, 1~3mg of ethylenediamine tetra-acetic acid, phenmethylol 1
~3mg；
The preparation method of the parenteral solution comprises the following steps：
(1) concentrated compounding：The methyl hydroxybenzoate and meglumine for weighing recipe quantity are added in water for injection, and stirring and dissolving uses 0.1mol/
L hydrochloric acid solution adjusts pH value to 6.0, add the natrium adetate of recipe quantity, vitamin C, ethylenediamine tetra-acetic acid, phenmethylol and
(S)-Esomeprazole stirring and dissolving, then with 0.1mol/L hydrochloric acid solution regulation regulation pH value
To 5.0, concentrated wiring liquid is obtained；
(2) it is dilute to match somebody with somebody：Concentrated wiring liquid water for injection constant volume is taken, is filtered with 0.45 μm of filter membrane, filtrate is collected；
(3) it is filling：After the assay was approved upper streamline carry out it is filling, buffered when filling the position level height ratio of fluid reservoir with
High 10cm~the 15cm of position level height of liquid nozzle；
(4) sterilize：Canned peace is cutd open into semi-finished product feeding steam sterilization pan sterilizing, sterilizing program：With 10 DEG C/min's
Heating rate is warming up to 121 DEG C, and sterilize 15min at 121 DEG C；Then compressed air air blast, with 3~5 DEG C/min cooling speed
8~12min of rate is cooled to 70~80 DEG C；Cooling water is used again, and 30 are cooled to 2~3 DEG C/min 15~18min of rate of temperature fall
DEG C, sterilizing is completed；Produce (S)-Esomeprazole parenteral solution.
Further, following supplementary material is contained in every mL parenteral solutions：(S)-Esomeprazole
200mg, natrium adetate 0.05mg, methyl hydroxybenzoate 4.5mg, meglumine 13mg, vitamin C 1.5mg, ethylenediamine tetra-acetic acid
2.5mg, phenmethylol 1.5mg.
Further, the concentrated compounding process of the step (1) need to lead to nitrogen processing, and nitrogen flow is 0.03~0.08L/min；It is described
Fluid reservoir is buffered in the pouring process of step (3) needs nitrogen charging to handle, and pouring process need to be filled with the nitrogen of purity 99.99% so that tank
Oxygen content in interior water for injection is no more than 0.01%.
The beneficial effects of the present invention are：
Froth breaking effect and natrium adetate, the hydrotropy stabilization of meglumine of the present invention using methyl hydroxybenzoate, preparation
(S)-Esomeprazole parenteral solution is non-foaming, does not have decoction adhesion problems, and product yield is high, and
A certain amount of vitamin C and ethylenediamine tetra-acetic acid are added, coordinates specific sterilization process, may be such that (S) -4- hydroxyls of preparation
Base -2- oxo-1-pyrrolidine ethanamide parenteral solutions have good stability, are difficult to be oxidized, and product is total miscellaneous in sterilization process
Matter increase is less, adds a certain amount of phenmethylol, can mitigate patient's injection pain sense, good patient compliance.
Embodiment
In order that the purpose of the present invention, technical scheme and beneficial effect are clearer, below by the preferred reality of the present invention
Example is applied to be described in detail.
Embodiment 1
The prescription of (S)-Esomeprazole parenteral solution of embodiment 1 is as shown in the table：
The preparation method of (S)-Esomeprazole parenteral solution of embodiment 1, including following step
Suddenly：
(1) concentrated compounding：The methyl hydroxybenzoate and meglumine for weighing recipe quantity are added in water for injection, and stirring and dissolving uses 0.1mol/
L hydrochloric acid solution adjusts pH value to 6.0, add the natrium adetate of recipe quantity, vitamin C, ethylenediamine tetra-acetic acid, phenmethylol and
(S)-Esomeprazole stirring and dissolving, then with 0.1mol/L hydrochloric acid solution regulation regulation pH value
To 5.0, concentrated wiring liquid is obtained；Concentrated compounding process need to lead to nitrogen processing, and nitrogen flow is 0.03~0.08L/min；
(2) it is dilute to match somebody with somebody：Take concentrated wiring liquid to be settled to 1000mL with water for injection, filtered with 0.45 μm of filter membrane, collect filtrate；
(3) it is filling：After the assay was approved upper streamline carry out it is filling, buffered when filling the position level height ratio of fluid reservoir with
High 10cm~the 15cm of position level height of liquid nozzle；Fluid reservoir is buffered in pouring process needs nitrogen charging to handle, and pouring process is needed
The nitrogen of purity 99.99% is filled with so that the oxygen content in tank in water for injection is no more than 0.01%；
(4) sterilize：Canned peace is cutd open into semi-finished product feeding steam sterilization pan sterilizing, sterilizing program：With 10 DEG C/min's
Heating rate is warming up to 121 DEG C, and sterilize 15min at 121 DEG C；Then compressed air air blast, with 4 DEG C/min rate of temperature fall
10min is cooled to 80 DEG C；Cooling water is used again, is cooled to 30 DEG C with 3 DEG C/min rate of temperature fall 17min, sterilizing is completed；Produce
(S)-Esomeprazole parenteral solution.
Comparative example 1
(S)-Esomeprazole parenteral solution of comparative example 1 does not add methyl hydroxybenzoate, remaining
Component and preparation method are same as Example 1.
Comparative example 2
(S)-Esomeprazole parenteral solution of comparative example 2 does not add phenmethylol, remaining group
Divide and preparation method is same as Example 1.
Embodiment 2
The prescription of (S)-Esomeprazole parenteral solution of embodiment 2 is as shown in the table：
The preparation method of (S)-Esomeprazole parenteral solution of embodiment 2, including following step
Suddenly：
(1) concentrated compounding：The methyl hydroxybenzoate and meglumine for weighing recipe quantity are added in water for injection, and stirring and dissolving uses 0.1mol/
L hydrochloric acid solution adjusts pH value to 6.0, add the natrium adetate of recipe quantity, vitamin C, ethylenediamine tetra-acetic acid, phenmethylol and
(S)-Esomeprazole stirring and dissolving, then with 0.1mol/L hydrochloric acid solution regulation regulation pH value
To 5.0, concentrated wiring liquid is obtained；Concentrated compounding process need to lead to nitrogen processing, and nitrogen flow is 0.03~0.08L/min；
(2) it is dilute to match somebody with somebody：Take concentrated wiring liquid to be settled to 1000mL with water for injection, filtered with 0.45 μm of filter membrane, collect filtrate；
(3) it is filling：After the assay was approved upper streamline carry out it is filling, buffered when filling the position level height ratio of fluid reservoir with
High 10cm~the 15cm of position level height of liquid nozzle；Fluid reservoir is buffered in pouring process needs nitrogen charging to handle, and pouring process is needed
The nitrogen of purity 99.99% is filled with so that the oxygen content in tank in water for injection is no more than 0.01%；
(4) sterilize：Canned peace is cutd open into semi-finished product feeding steam sterilization pan sterilizing, sterilizing program：With 10 DEG C/min's
Heating rate is warming up to 121 DEG C, and sterilize 15min at 121 DEG C；Then compressed air air blast, with 4 DEG C/min rate of temperature fall
12min is cooled to 73 DEG C；Cooling water is used again, is cooled to 30 DEG C with 2.5 DEG C/min rate of temperature fall 17min, sterilizing is completed；Produce
(S)-Esomeprazole parenteral solution.
Comparative example 3
(S)-Esomeprazole parenteral solution of comparative example 3 does not add methyl hydroxybenzoate, remaining
Component and preparation method are same as Example 2.
Comparative example 4
(S)-Esomeprazole parenteral solution of comparative example 4 does not add phenmethylol, remaining group
Divide and preparation method is same as Example 2.
Embodiment 3
The prescription of (S)-Esomeprazole parenteral solution of embodiment 3 is as shown in the table：
The preparation method of (S)-Esomeprazole parenteral solution of embodiment 3, including following step
Suddenly：
(1) concentrated compounding：The methyl hydroxybenzoate and meglumine for weighing recipe quantity are added in water for injection, and stirring and dissolving uses 0.1mol/
L hydrochloric acid solution adjusts pH value to 6.0, add the natrium adetate of recipe quantity, vitamin C, ethylenediamine tetra-acetic acid, phenmethylol and
(S)-Esomeprazole stirring and dissolving, then with 0.1mol/L hydrochloric acid solution regulation regulation pH value
To 5.0, concentrated wiring liquid is obtained；Concentrated compounding process need to lead to nitrogen processing, and nitrogen flow is 0.03~0.08L/min；
(2) it is dilute to match somebody with somebody：Take concentrated wiring liquid to be settled to 1000mL with water for injection, filtered with 0.45 μm of filter membrane, collect filtrate；
(3) it is filling：After the assay was approved upper streamline carry out it is filling, buffered when filling the position level height ratio of fluid reservoir with
High 10cm~the 15cm of position level height of liquid nozzle；Fluid reservoir is buffered in pouring process needs nitrogen charging to handle, and pouring process is needed
The nitrogen of purity 99.99% is filled with so that the oxygen content in tank in water for injection is no more than 0.01%；
(4) sterilize：Canned peace is cutd open into semi-finished product feeding steam sterilization pan sterilizing, sterilizing program：With 10 DEG C/min's
Heating rate is warming up to 121 DEG C, and sterilize 15min at 121 DEG C；Then compressed air air blast, with 5 DEG C/min rate of temperature fall
9min is cooled to 76 DEG C；Cooling water is used again, is cooled to 30 DEG C with 3 DEG C/min rate of temperature fall 15min, sterilizing is completed；Produce
(S)-Esomeprazole parenteral solution.
Comparative example 5
(S)-Esomeprazole parenteral solution of comparative example 5 does not add methyl hydroxybenzoate, remaining
Component and preparation method are same as Example 3.
Comparative example 6
(S)-Esomeprazole parenteral solution of comparative example 6 does not add phenmethylol, remaining group
Divide and preparation method is same as Example 3.
Comparative example 7
The prescription of (S)-Esomeprazole parenteral solution of comparative example 7 lacks vitamin C and second
Ethylenediamine tetraacetic acid (EDTA), remaining component and preparation method are same as Example 1.
Comparative example 8
The sterilizing program of the step of comparative example 8 (4)：115 DEG C are warming up to 10 DEG C/min heating rate, at 115 DEG C
Sterilize 32min；Then 30 DEG C are naturally cooled to, sterilizing is completed；Remaining component and preparation method are same as Example 1.
First, long term test is investigated：
(S)-Esomeprazole parenteral solution made from embodiment 1-3 is packed by listing, put
In the long-term case that keeps sample, certain time sampling is tested to investigation project.
Long term test temperature：20 ± 2 DEG C, humidity：RH60% ± 10%, investigates the time：0th, 12,24 months, inspection target：Outside
See character, visible foreign matters, pH, relevant material, content.
Long term test stability is recorded：
Result, (S) -4- hydroxyls -2- OXo-1-pyrrolidine acetyl made from embodiment 1-3 are investigated from long term test
Amine injection product stability is good, and the term of validity is long, and product impurity is few, and indices meet production requirement.
2nd, yield is calculated：
Embodiment 1-3 and the product yield of comparative example 1,3,5 are calculated, it is as a result as follows：
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example 1 | Comparative example 3 | Comparative example 5 | |
| Theoretical yield (bottle) | 200 | 200 | 200 | 200 | 200 | 200 |
| Actual production (bottle) | 170 | 169 | 165 | 125 | 130 | 131 |
| Yield (%) | 85 | 84.5 | 82.5 | 62.5 | 65 | 65.5 |
From yield result of calculation, because comparative example in pouring process has decoction to stick in ampoule bottleneck, cause ampoule
When bottle height temperature is sealed, stick in the decoction carbonization of bottleneck and make parenteral solution visible foreign matters unqualified, reduce product yield；And it is real
Example is applied because decoction is non-foaming, in the absence of the situation of adhesion ampoule bottleneck, its yield is greatly improved.
3rd, impurity increment contrast test：
To embodiment 1 and comparative example 7-8, sampling detects relevant material afterwards before sterilization respectively, investigates sterilization process to having
The influence of material is closed, it is as a result as follows：
| Relevant material before sterilizing | Relevant material after sterilizing | The relevant material incrementss of sterilization process | |
| Embodiment 1 | 0.17% | 0.22% | 0.05% |
| Comparative example 7 | 0.21% | 0.38% | 0.17% |
| Comparative example 8 | 0.18% | 0.30% | 0.12% |
From impurity increment comparative test result, a certain amount of vitamin C and ethylenediamine tetrem are added in embodiment 1
Acid, coordinates specific sterilization process so that product impurity incrementss in sterilization process are only 0.05%, hence it is evident that better than comparative example
7 and comparative example 8.
4th, pain contrast test：
Small white mouse is taken, (S)-Esomeprazole parenteral solution is subcutaneously injected, observation small white mouse is
It is no to occur writhing response, occur the probability of writhing response to judge the power of pain in injection process according to mouse, implement
The injection liquid samples of example 1-3 and comparative example 2,4,6 respectively repeat 30 experiments；As a result it is as follows：
| Experiment sample (mouse) | Generation writhing response number of individuals | Writhing response incidence | |
| Embodiment 1 | 30 | 8 | 26.7% |
| Comparative example 2 | 30 | 23 | 76.7% |
| Embodiment 2 | 30 | 9 | 30.0% |
| Comparative example 4 | 30 | 22 | 73.3% |
| Embodiment 3 | 30 | 8 | 26.7% |
| Comparative example 6 | 30 | 22 | 73.3% |
From pain comparative test result, embodiment 1-3 (S)-Esomeprazole
Parenteral solution is markedly less than comparative example due to adding the pain in a certain amount of phenmethylol, injection process.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical
Cross above preferred embodiment the present invention is described in detail, it is to be understood by those skilled in the art that can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (3)
1. a kind of stablize oxidation resistant (S)-Esomeprazole parenteral solution, it is characterised in that：Per mL
Contain following supplementary material in parenteral solution：(S) -180 ~ 220mg of Esomeprazole, natrium adetate
0.01 ~ 0.1mg, 4 ~ 5mg of methyl hydroxybenzoate, 10 ~ 16mg of meglumine, 1 ~ 2mg of vitamin C, 1 ~ 3mg of ethylenediamine tetra-acetic acid, phenmethylol
1~3mg；
The preparation method of the parenteral solution comprises the following steps：
（1）Concentrated compounding：The methyl hydroxybenzoate and meglumine for weighing recipe quantity are added in water for injection, stirring and dissolving, with 0.1mol/L's
Hydrochloric acid solution adjusts pH value to 6.0, add the natrium adetate of recipe quantity, vitamin C, ethylenediamine tetra-acetic acid, phenmethylol and
(S)-Esomeprazole stirring and dissolving, then with 0.1mol/L hydrochloric acid solution regulation regulation pH value
To 5.0, concentrated wiring liquid is obtained；
（2）It is dilute to match somebody with somebody：Concentrated wiring liquid water for injection constant volume is taken, is filtered with 0.45 μm of filter membrane, filtrate is collected；
（3）It is filling：Upper streamline carries out filling, the position level height ratio and decoction of buffering fluid reservoir when filling after the assay was approved
High 10cm ~ the 15cm of position level height of nozzle；
（4）Sterilizing：Canned peace is cutd open into semi-finished product feeding steam sterilization pan sterilizing, sterilizing program：With 10 DEG C/min heating
Speed is warming up to 121 DEG C, and sterilize 15min at 121 DEG C；Then compressed air air blast, with 3 ~ 5 DEG C/min rate of temperature fall 8 ~
12min is cooled to 70 ~ 80 DEG C；Cooling water is used again, is cooled to 30 DEG C with 2 ~ 3 DEG C/min 15 ~ 18min of rate of temperature fall, has been sterilized
Into；Produce (S)-Esomeprazole parenteral solution.
2. according to claim 1 stablize oxidation resistant (S)-Esomeprazole parenteral solution,
It is characterized in that：Contain following supplementary material in per mL parenteral solutions：(S)-Esomeprazole 200mg,
Natrium adetate 0.05mg, methyl hydroxybenzoate 4.5mg, meglumine 13mg, vitamin C 1.5mg, ethylenediamine tetra-acetic acid 2.5mg, benzene
Methanol 1.5mg.
3. the preparation method of parenteral solution according to claim 1, it is characterised in that：The step（1）Concentrated compounding process need
Logical nitrogen processing, nitrogen flow is 0.03 ~ 0.08L/min；The step（3）Pouring process in buffering fluid reservoir need at nitrogen charging
Reason, pouring process need to be filled with the nitrogen of purity 99.99% so that the oxygen content in tank in water for injection is no more than 0.01%.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610240685.6A CN107303270A (en) | 2016-04-18 | 2016-04-18 | It is a kind of to stablize oxidation resistant (S)-Esomeprazole parenteral solution |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610240685.6A CN107303270A (en) | 2016-04-18 | 2016-04-18 | It is a kind of to stablize oxidation resistant (S)-Esomeprazole parenteral solution |
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| CN107303270A true CN107303270A (en) | 2017-10-31 |
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|---|---|---|---|
| CN201610240685.6A Withdrawn CN107303270A (en) | 2016-04-18 | 2016-04-18 | It is a kind of to stablize oxidation resistant (S)-Esomeprazole parenteral solution |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009039460A2 (en) * | 2007-09-21 | 2009-03-26 | Acadia Pharmaceuticals, Inc. | Co-administration of pimavanserin with other agents |
| CN101766597A (en) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | Injection preparation with levo-oxiracetam as active component |
-
2016
- 2016-04-18 CN CN201610240685.6A patent/CN107303270A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009039460A2 (en) * | 2007-09-21 | 2009-03-26 | Acadia Pharmaceuticals, Inc. | Co-administration of pimavanserin with other agents |
| CN101766597A (en) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | Injection preparation with levo-oxiracetam as active component |
Non-Patent Citations (1)
| Title |
|---|
| 颜素华等: "奥拉西坦注射液的研制", 《中国现代医学杂志》 * |
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Application publication date: 20171031 |