CN106377511A - S-oxiracetam sterile injectable powder and preparation method thereof - Google Patents
S-oxiracetam sterile injectable powder and preparation method thereof Download PDFInfo
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- CN106377511A CN106377511A CN201510458373.8A CN201510458373A CN106377511A CN 106377511 A CN106377511 A CN 106377511A CN 201510458373 A CN201510458373 A CN 201510458373A CN 106377511 A CN106377511 A CN 106377511A
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Abstract
An S-oxiracetam sterile injectable powder is characterized in that the S-oxiracetam sterile injectable powder is prepared with S-oxiracetam, L-serine and mannitol as raw and auxiliary materials and through the steps of concentrated preparation, dilute preparation, freeze-drying and capping; the S-oxiracetam sterile injectable powder prepared according to the preparation method has a fixed shape, has no dry shrinkage or bubbling phenomena in the freeze drying preparation process, has the advantages of good product homogeneity and consistent characters of upper and lower layers, has fewer impurities, has the total impurities of less than 0.24%, is conducive to improvement of the safety of drug use, reduces adverse drug reactions, has good product stability, and has the shelf life as long as 24 months.
Description
Technical field
The invention mainly relates to pharmaceutical technology field is and in particular to a kind of levo-oxiracetam sterilized powder injection and preparation method thereof.
Background technology
Levo-oxiracetam chemical name is：S- (-) -4- hydroxyl -2- oxo-pyrrolidine-N- acetamide, it is white micro-crystals sprills, 135～136 DEG C of fusing point, -36 ° of optical rotation (C=1.00in water), the dissolubility of levo-oxiracetam is substantially better than raceme.Chemical structural formula is as follows：
In 1987 in Italy's listing, the dosage form of listing is tablet to this medicine, 800mg；Capsule, 800mg；Injection, 1g/5ml.Domestic at present only oxiracetam capsule and injection listing, and main active used is racemic modification.Ye Lei etc. mention in Publication No. CN 103735545 A patent levo-oxiracetam to alcoholism caused by stupor promoting wakening substantially, and dextrorotation oxiracetam does not act on substantially, and the above-mentioned rush of levo-oxiracetam is waken up 2 times that effect is racemization oxiracetam；Levo-oxiracetam is all notable to the promoting wakening of stupor caused by wound, anesthesia.Zhang Feng etc. disclose in the patent of Publication No. CN 103599101 A levo-oxiracetam to hydraulic pressure and freely falling body caused by traumatic brain injury learning and memory in rats cognitive dysfunction all improve significantly, its drug effect be far above dextrorotation oxiracetam.And 200mg/kg levo-oxiracetam is suitable with the effect of 400mg/kg oxiracetam.Pharmacokinetic study results show：Levo-oxiracetam and dextrorotation oxiracetam no obvious chiral inversion in beasle dog body.Beasle dog single intravenous injection gives the equal no significant difference of main pharmacokinetic parameters of levo-oxiracetam in blood plasma after the left-handed and racemization oxiracetam of 2 multiple doses.The result of the tests such as safe pharmacology, anxious malicious, long poison show, under isodose level, levo-oxiracetam and the toxicity no significant difference to animal subject or cell for the oxiracetam.Above-mentioned preclinical result of study shows, levo-oxiracetam is the main active playing drug effect in oxiracetam body, is used alone this product and can reduce Clinical practice dosage, reduces potential toxicity.
Existing injection levo-oxiracetam sterilized powder its be primarily present no solid shape, be difficult to form skeleton, drying shrinkage and bubbling phenomenon easily occur, product stability is poor, and shelf life is short, and product homogeneity is bad, the problems such as levels character is inconsistent.
Content of the invention
It is an object of the invention to provide a kind of have the good levo-oxiracetam sterilized powder injection of solid form, good stability, product homogeneity.
Another object of the present invention is to providing the preparation method of above-mentioned levo-oxiracetam sterilized powder injection.
The purpose of the present invention is realized by following technical measures：
A kind of levo-oxiracetam sterilized powder injection, it is characterised in that it is with levo-oxiracetam as raw material, adds a certain amount of excipient and is obtained；Wherein said excipient is one or more of sucrose, trehalose, Mannitol, Lactose, glucose, maltose, glucosan, albumin, Polyethylene Glycol, glycerol, L-Serine, sodium glutamate, alanine, glycine, sarcosine, phosphate, acetate, citrate.
Inventor is found to select the Composite excipient of a certain proportion of L-Serine and Mannitol composition in composition described above, is coordinated specific Freeze Drying Technique again by many experiments, and above-mentioned levo-oxiracetam sterilized powder injection can be made to have solid shape, easily form that skeleton, product homogeneity be good, levels character is consistent；Above-mentioned levo-oxiracetam sterilized powder injection it is characterised in that it is with levo-oxiracetam, L-Serine, Mannitol as supplementary material, by dense join, dilute join, lyophilization and roll lid step be obtained；Wherein said lyophilization step is quickly heat conduction oil temperature to be refrigerated to -40 DEG C, keep constant temperature 60 minutes, it is warming up to -10 DEG C with 5 DEG C/h, keep constant temperature 80 minutes, it is being quickly cooled to -40 DEG C, cryostat 120 minutes, then evacuation drying, it is warming up to 10 DEG C/h, -10 DEG C of constant temperature 150 minutes；It is warming up to 0 DEG C with 4 DEG C/h, 0 DEG C of constant temperature 300 minutes；Be warming up to 10 DEG C with 5 DEG C/h, 10 DEG C of constant temperature 240 minutes, be warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, simultaneously front case vacuum fall reach 10Pa/10 timesharing, lyophilizing terminates.
Further above-mentioned levo-oxiracetam sterilized powder injection is it is characterised in that it is to be obtained by the supplementary material of following weight percents：Levo-oxiracetam 57%～68%, L-Serine 18%～23%, Mannitol 12%～22%.
Inventor finds in research process, add a certain amount of Macrogol 2000, product can be made to be less prone to drying shrinkage and bubbling phenomenon, and can make shelf life extend, above-mentioned levo-oxiracetam sterilized powder injection it is characterised in that：Levo-oxiracetam 59%～63%, L-Serine 19%～22%, Mannitol 13%～18%, Macrogol 2000 4%～6%.
Most preferably, above-mentioned levo-oxiracetam sterilized powder injection is it is characterised in that it is to be obtained by the supplementary material of following significant percentage：Levo-oxiracetam 59%～61%, L-Serine 20%～21%, Mannitol 15%～17%, Macrogol 2000 4%～6%.
A kind of preparation method of levo-oxiracetam freeze-dried powder is it is characterised in that it is obtained as follows：
1. dense join：The levo-oxiracetam of recipe quantity, excipient are placed in container, add the sterilized water for injection stirring of 5 times of weight portions of levo-oxiracetam, after dissolving, add the needle-use activated carbon of mass fraction 0.5%, stir 30min, subsequently filtered with 0.45 micrometer Millipore filter membrane, collect filtrate, standby；
2. dilute join：Add sterilized water for injection to recipe quantity in filtrate, adjust pH to 7.0 with hydrochloric acid or sodium hydroxide, subsequently with 0.22 micron of microporous filter membrane aseptic filtration, take the qualified rear fill of filtrate to be sub-packed in sterile glass vials, standby；
3. lyophilization：Quickly heat conduction oil temperature is refrigerated to -40 DEG C, keeps constant temperature 60 minutes, be warming up to -10 DEG C with 5 DEG C/h, keep constant temperature 80 minutes, be quickly cooled to -40 DEG C, cryostat 120 minutes, then evacuation is dried, and is warming up to 10 DEG C/h, -10 DEG C of constant temperature 150 minutes；It is warming up to 0 DEG C with 4 DEG C/h, 0 DEG C of constant temperature 300 minutes；Be warming up to 10 DEG C with 5 DEG C/h, 10 DEG C of constant temperature 240 minutes, be warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, simultaneously front case vacuum fall reach 10Pa/10 timesharing, lyophilizing terminates.
4. roll lid：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, obtains final product.
The present invention has following beneficial effect：
Levo-oxiracetam sterilized powder injection of the present invention have solid shape, in lyophilizing preparation process no drying shrinkage and bubbling phenomenon, product homogeneity is good, levels character is consistent, impurity is few, its total impurities is less than 0.24%, is conducive to improving the safety that medicine uses, reduces adverse effect, product stability is good, and shelf life is up to 24 months.
Specific embodiment
Below by embodiment, the present invention is specifically described; be necessary it is pointed out here that be that following examples are served only for the present invention is further described; it is not intended that limiting the scope of the invention; without departing from the spirit and substance of the case in the present invention; the modification that the inventive method, step or condition are made or replacement, belong to the scope of the present invention.
Embodiment 1
A kind of levo-oxiracetam sterilized powder injection, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| L-Serine | 35g |
| Mannitol | 27g |
| Macrogol 2000 | 7g |
Make 1000 bottles
Preparation process：
1. dense join：The levo-oxiracetam of recipe quantity, excipient are placed in container, add the sterilized water for injection stirring of 5 times of weight portions of levo-oxiracetam, after dissolving, add the needle-use activated carbon of mass fraction 0.5%, stir 30min, subsequently filtered with 0.45 micrometer Millipore filter membrane, collect filtrate, standby；
2. dilute join：Add sterilized water for injection to recipe quantity in filtrate, adjust pH to 7.0 with hydrochloric acid or sodium hydroxide, subsequently with 0.22 micron of microporous filter membrane aseptic filtration, take the qualified rear fill of filtrate to be sub-packed in sterile glass vials, standby；
3. lyophilization：Quickly heat conduction oil temperature is refrigerated to -40 DEG C, keep constant temperature 60 minutes, it is warming up to -10 DEG C with 5 DEG C/h, keep constant temperature 80 minutes, it is being quickly cooled to -40 DEG C, cryostat 120 minutes, then evacuation drying, it is warming up to 10 DEG C/h, -10 DEG C of constant temperature 150 minutes, is warming up to 0 DEG C with 4 DEG C/h, 0 DEG C of constant temperature 300 minutes, it is warming up to 10 DEG C with 5 DEG C/h, 10 DEG C of constant temperature 240 minutes, is warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, front case vacuum fall reaches 10Pa/10 timesharing simultaneously, and lyophilizing terminates.
4. roll lid：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, obtains final product.
Embodiment 2
A kind of levo-oxiracetam sterilized powder injection, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| L-Serine | 33g |
| Mannitol | 25g |
| Macrogol 2000 | 7g |
Make 1000 bottles
Preparation process：Preparation technology according to embodiment 1 is obtained.
Embodiment 3
A kind of levo-oxiracetam sterilized powder injection, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| L-Serine | 34g |
| Mannitol | 26g |
| Macrogol 2000 | 7g |
Make 1000 bottles
Preparation process：Preparation technology according to embodiment 1 is obtained.
Embodiment 4-6：A kind of levo-oxiracetam sterilized powder injection, is prepared by the supplementary material of following weight, preparation method is with embodiment 1：
| Embodiment | Levo-oxiracetam | L-Serine | Mannitol | Macrogol 2000 |
| 4 | 100g | 35g | 26g | 8g |
| 5 | 100g | 34g | 26g | 7g |
| 6 | 100g | 35g | 27g | 9g |
The beneficial effect of invention medicine in order to be better understood from the present invention, is expanded on further below by way of stability test of the present invention, rather than limitation of the present invention.
Experiment one：A kind of present invention levo-oxiracetam sterilized powder injection stability experiment
Experiment material：
Levo-oxiracetam sterilized powder injection sample：It is obtained for embodiment 1
Acceleration study method：The levo-oxiracetam sterilized powder injection that embodiment 1 is obtained presses listing packaging, puts in Acceleration study case, and certain time samples, and investigation project is tested.
Acceleration study temperature：40±2℃
Humidity：RH75% ± 5%
The investigation time：0th, 1,2,3, June
Inspection target：Character, visible foreign matters, pH, relevant material, content, sterility test
Accelerated test stability record：
Acceleration study result shows：Accelerate June sample suitable with 0 month sample items Testing index quality, show this product Acceleration study June, quality keeps stable, and this product stability is preferable.
Long-term experiment method：The levo-oxiracetam sterilized powder injection that embodiment 1 is obtained presses listing packaging, puts and keeps sample in case for a long time, and certain time samples, and investigation project is tested.
Acceleration study temperature：25±2℃
Humidity：RH60% ± 10%
The investigation time：0th, 3,6,9,12,18,24 months
Inspection target：Character, visible foreign matters, pH, relevant material, content, sterility test
Long term test stability record：
Long term test shows：24 months character of this product long term test, visible foreign matters, pH value, relevant material, content and sterility test indices all no significant changes, all meet every relevant regulations of production quality standard draft.24 months steady qualities of this product long term test, therefore minimum 24 months of this product shelf life, long term test is still during continuing to investigate.
Claims (4)
1. a kind of levo-oxiracetam sterilized powder injection is it is characterised in that it is with levo-oxiracetam, L-Serine, Mannitol as supplementary material, by dense join, dilute join, lyophilization and roll lid step and be obtained；Wherein said lyophilization step is quickly heat conduction oil temperature to be refrigerated to -40 DEG C, keep constant temperature 60 minutes, it is warming up to -10 DEG C with 5 DEG C/h, keep constant temperature 80 minutes, it is being quickly cooled to -40 DEG C, cryostat 120 minutes, then evacuation drying, it is warming up to 10 DEG C/h, -10 DEG C of constant temperature 150 minutes；It is warming up to 0 DEG C with 4 DEG C/h, 0 DEG C of constant temperature 300 minutes；Be warming up to 10 DEG C with 5 DEG C/h, 10 DEG C of constant temperature 240 minutes, be warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, simultaneously front case vacuum fall reach 10Pa/10 timesharing, lyophilizing terminates.
2. levo-oxiracetam sterilized powder injection as claimed in claim 1 is it is characterised in that it is to be obtained by the supplementary material of following weight percents：Levo-oxiracetam 57% ~ 68%, L-Serine 18% ~ 23%, Mannitol 12% ~ 22%.
3. levo-oxiracetam sterilized powder injection as claimed in claim 2 is it is characterised in that it is to be obtained by the supplementary material of following weight percents：Levo-oxiracetam 59% ~ 63%, L-Serine 19% ~ 22%, Mannitol 13% ~ 18%, Macrogol 2000 4% ~ 6%.
4. the preparation method of the injection levo-oxiracetam sterilized powder as any one of claim 1 ~ 3 is it is characterised in that it is to prepare as follows：
A. dense join：The levo-oxiracetam of recipe quantity, excipient are placed in container, add the sterilized water for injection stirring of 5 times of weight portions of levo-oxiracetam, after dissolving, add the needle-use activated carbon of mass fraction 0.5%, stir 30min, subsequently filtered with 0.45 micrometer Millipore filter membrane, collect filtrate, standby；
B. dilute join：Add sterilized water for injection to recipe quantity in filtrate, adjust pH to 7.0 with hydrochloric acid or sodium hydroxide, subsequently with 0.22 micron of microporous filter membrane aseptic filtration, take the qualified rear fill of filtrate to be sub-packed in sterile glass vials, standby；
C. lyophilization：Quickly heat conduction oil temperature is refrigerated to -40 DEG C, keeps constant temperature 60 minutes, be warming up to -10 DEG C with 5 DEG C/h, keep constant temperature 80 minutes, be quickly cooled to -40 DEG C, cryostat 120 minutes, then evacuation is dried, and is warming up to 10 DEG C/h, -10 DEG C of constant temperature 150 minutes；It is warming up to 0 DEG C with 4 DEG C/h, 0 DEG C of constant temperature 300 minutes；Be warming up to 10 DEG C with 5 DEG C/h, 10 DEG C of constant temperature 240 minutes, be warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, simultaneously front case vacuum fall reach 10Pa/10 timesharing, lyophilizing terminates；
D. roll lid：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, obtains final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510458373.8A CN106377511A (en) | 2015-07-30 | 2015-07-30 | S-oxiracetam sterile injectable powder and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510458373.8A CN106377511A (en) | 2015-07-30 | 2015-07-30 | S-oxiracetam sterile injectable powder and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN106377511A true CN106377511A (en) | 2017-02-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510458373.8A Pending CN106377511A (en) | 2015-07-30 | 2015-07-30 | S-oxiracetam sterile injectable powder and preparation method thereof |
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|---|---|
| CN (1) | CN106377511A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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2015
- 2015-07-30 CN CN201510458373.8A patent/CN106377511A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
|---|
| 罗明生，等: "《药剂辅料大全》", 31 January 2006, 四川科学技术出版社 * |
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Effective date of registration: 20170824 Address after: 400042 Chongqing city Yubei District Qinye Road No. 9 Applicant after: Chongqing Runze Pharmaceutical Co., Ltd. Address before: 400030 Chongqing city Shapingba District Yubei Road No. 50 of No. 13-15-6A Applicant before: DONGZE PHARMACEUTICAL SCIENCE AND TECHNOLOGY CO., LTD. |
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Application publication date: 20170208 |
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