CN107432861B - Levo-oxiracetam freeze-dried composition for injection and preparation method thereof - Google Patents
Levo-oxiracetam freeze-dried composition for injection and preparation method thereof Download PDFInfo
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- CN107432861B CN107432861B CN201610356672.5A CN201610356672A CN107432861B CN 107432861 B CN107432861 B CN 107432861B CN 201610356672 A CN201610356672 A CN 201610356672A CN 107432861 B CN107432861 B CN 107432861B
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
The invention discloses a levo-oxiracetam freeze-dried composition for injection and a preparation method thereof; the freeze-dried composition contains the following raw and auxiliary materials in percentage by weight: 50% -60% of levo-oxiracetam, 20% -25% of L-serine, 10% -17% of mannitol, 5% -7% of sodium glutamate and 5% -10% of sodium bisulfite; the preparation method of the L-oxiracetam freeze-dried composition for injection comprises the steps of concentrated preparation, diluted preparation, freeze drying, capping and the like. According to the invention, the specific excipient combination is utilized, so that the prepared levo-oxiracetam freeze-dried composition has a fixed shape, no bottle spraying phenomenon is caused in the freeze-drying process, the product stability is good, and after the levo-oxiracetam freeze-dried composition is dissolved into glucose injection or sodium chloride injection to prepare an intravenous drip solution, insoluble particles are remarkably reduced, the safety of medicine use is improved, and adverse medicine reactions are reduced.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a levo-oxiracetam freeze-dried composition for injection and a preparation method thereof.
Background
An intelligence promoting medicine is also called as brain activating element, and is a novel central nervous system medicine for promoting learning and enhancing memory. Nootropic agents require selective action on the cerebral cortex and have the characteristics of selective activation, protection and promotion of functional recovery of damaged nerve cells. One difference with other nerve drugs is that their above-mentioned action does not go through the reticular system or olfactory bulb, but directly acts on the cortex. Neither behavior nor sedation and excitement is affected, so that the medicines have attracted extensive attention and interest, and the demand for the medicines is increasing.
Oxiracetam (oxiracetam, CAS No.: 62613-82-5) has the chemical name of 4-hydroxy-2-oxo-1-pyrrolidine acetamide, is an anti-hypoxia nootropic drug (the compound is disclosed in US4118396) which is synthesized for the first time in 1974 by ISFS. P.A. company of Italy, is a cyclic GABOB derivative, can promote the synthesis of phosphorylcholine and phosphorylethanolamine, promote brain metabolism, penetrate blood brain barrier, has stimulation effect on specific central nervous pathways, can improve intelligence and memory, has better curative effect on cerebrovascular diseases, brain trauma, brain tumor, intracranial infection, brain degeneration diseases and the like, and has extremely low toxicity, no mutagenic effect, carcinogenic effect and reproductive toxicity. The chemical structure and preparation of oxiracetam is disclosed in US4118396 by Giorgio et al, and the pharmaceutical efficacy of oxiracetam in the S configuration (levo) is shown in the clinical results in WO9306826A by Chiodini et al, which is stronger than that in the R configuration (dextro), with oxiracetam and levooxiracetam structures shown below.
However, the existing levo-oxiracetam freeze-dried powder injection for injection has no fixed shape, is not easy to form a framework, is easy to generate a bottle spraying phenomenon in a freeze-drying process, and has the problem of poor product stability, before clinical use, the levo-oxiracetam freeze-dried powder injection needs to be dissolved into 100-250 ml of 5% glucose injection or 0.9% sodium chloride injection to be prepared into an intravenous drip solution for use, after the levo-oxiracetam freeze-dried powder injection is prepared into the intravenous drip solution, insoluble particles of the levo-oxiracetam freeze-dried powder injection increase along with the prolonging of the standing time, and thus great potential safety hazards are brought to clinical use.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a lyophilized levetiracetam composition for injection having a fixed shape, no spray bottle phenomenon during lyophilization, and good product stability, and insoluble microparticles are reduced after preparation into an intravenous drip solution, and a preparation method thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
the freeze-dried composition of the levo-oxiracetam for injection comprises the following raw and auxiliary materials in percentage by weight: 50-60% of levo-oxiracetam, 20-25% of L-serine, 10-17% of mannitol, 5-7% of sodium glutamate and 5-10% of sodium bisulfite.
Further, the freeze-dried composition contains the following raw and auxiliary materials in percentage by weight: 53% of levo-oxiracetam, 22% of L-serine, 12% of mannitol, 6% of sodium glutamate and 7% of sodium bisulfite.
The preparation method of the levo-oxiracetam freeze-dried composition for injection comprises the following steps:
(1) concentration and preparation: placing the raw and auxiliary materials in a container according to the prescription amount, adding 10 weight-times of sterilized water for injection of levetiracetam, stirring, dissolving, adding 0.1 mass percent of injectable activated carbon, stirring for 30min, filtering with a 0.45-micron microporous filter membrane, and collecting the filtrate for later use;
(2) diluting and preparing: adding sterile injection water into the filtrate to 1000 times of the volume of the filtrate, adjusting the pH value to 3.2-3.6 by using 0.1mol/L hydrochloric acid or 0.1mol/L sodium hydroxide, then performing sterile filtration by using a 0.22 micron microporous filter membrane, filling and subpackaging the qualified filtrate in a sterile glass bottle for later use;
(3) and (3) freeze drying: freeze-drying the liquid medicine in the sterile glass bottle in a freeze dryer;
(4) and (3) rolling a cover: and cleaning the aluminum-plastic combined cover, sterilizing, drying, and rolling to obtain the aluminum-plastic combined cover.
Further, in the step (3), the step of freeze-drying is: rapidly freezing to-40 deg.C, and maintaining for 180 min; then vacuumizing and drying, heating to-10 ℃ at the speed of 15 ℃/h, and keeping the constant temperature of-10 ℃ for 120 minutes; heating to 0 ℃ at the speed of 5 ℃/h, and keeping the temperature at 0 ℃ for 320 minutes; heating to 10 ℃ at the speed of 5 ℃/h, and keeping the temperature of 10 ℃ for 240 minutes; heating to 30 deg.C at 10 deg.C/hr, maintaining the temperature at 30 deg.C for 60 min, and vacuum-reducing the front box to 10Pa/10 min to complete the freeze-drying.
The invention has the beneficial effects that:
according to the invention, the specific excipient combination is utilized, so that the prepared levo-oxiracetam freeze-dried composition has a fixed shape, no bottle spraying phenomenon is caused in the freeze-drying process, the product stability is good, and after the levo-oxiracetam freeze-dried composition is dissolved into glucose injection or sodium chloride injection to prepare an intravenous drip solution, insoluble particles are remarkably reduced, the safety of medicine use is improved, and adverse medicine reactions are reduced.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, preferred embodiments of the present invention will be described in detail below.
Example 1
The formulation of the lyophilized composition of levo-oxiracetam for injection of example 1 is shown in the following table:
| prescription | Weight percent of |
| Levo-oxiracetam | 50％ |
| L-serine | 25％ |
| Mannitol | 15％ |
| Glutamic acid sodium salt | 5％ |
| Sodium bisulfite | 5％ |
The preparation method of the lyophilized composition of levo-oxiracetam for injection of example 1 comprises the following steps:
(1) concentration and preparation: placing the raw and auxiliary materials in a container according to the prescription amount, adding 10 weight-times of sterilized water for injection of levetiracetam, stirring, dissolving, adding 0.1 mass percent of injectable activated carbon, stirring for 30min, filtering with a 0.45-micron microporous filter membrane, and collecting the filtrate for later use;
(2) diluting and preparing: adding sterile injection water into the filtrate to 1000 times of the volume of the filtrate, adjusting the pH value to 3.2-3.6 by using 0.1mol/L hydrochloric acid or 0.1mol/L sodium hydroxide, then performing sterile filtration by using a 0.22 micron microporous filter membrane, filling and subpackaging the qualified filtrate in a sterile glass bottle for later use;
(3) and (3) freeze drying: placing the liquid medicine subpackaged in the sterile glass bottles in a freeze dryer, quickly freezing the liquid medicine to-40 ℃, and keeping the temperature for 180 minutes in the whole process; then vacuumizing and drying, heating to-10 ℃ at the speed of 15 ℃/h, and keeping the constant temperature of-10 ℃ for 120 minutes; heating to 0 ℃ at the speed of 5 ℃/h, and keeping the temperature at 0 ℃ for 320 minutes; heating to 10 ℃ at the speed of 5 ℃/h, and keeping the temperature of 10 ℃ for 240 minutes; heating to 30 ℃ at the speed of 10 ℃/h, keeping the temperature of 30 ℃ for 60 minutes, simultaneously reducing the vacuum of the front box to 10Pa/10 minutes, and finishing the freeze-drying;
(4) and (3) rolling a cover: and cleaning the aluminum-plastic combined cover, sterilizing, drying, and rolling to obtain the aluminum-plastic combined cover.
Example 2
The formulation of the lyophilized composition of levo-oxiracetam for injection of example 2 is shown in the following table:
| prescription | Weight percent of |
| Levo-oxiracetam | 53％ |
| L-serine | 22％ |
| Mannitol | 12％ |
| Glutamic acid sodium salt | 6％ |
| Sodium bisulfite | 7％ |
The preparation method of the lyophilized composition of levo-oxiracetam for injection of example 2 is the same as that of example 1.
Example 3
The formulation of the lyophilized composition of levo-oxiracetam for injection of example 3 is shown in the following table:
| prescription | Weight percent of |
| Levo-oxiracetam | 54％ |
| L-serine | 20％ |
| Mannitol | 10％ |
| Glutamic acid sodium salt | 6％ |
| Sodium bisulfite | 10％ |
The preparation method of the lyophilized composition of levooxiracetam for injection of example 3 is the same as that of example 1.
Comparative example 1
The lyophilized composition of levo-oxiracetam for injection of comparative example 1 was prepared without adding sodium bisulfite, and the remaining components and preparation method were the same as those of example 2.
Firstly, character investigation:
the freeze-dried compositions of levo-oxiracetam for injection prepared in examples 1 to 3 were sampled and examined for the following items: character, visible foreign matter, pH, related substances, content, and sterility.
From the results of the property examination, the freeze-dried composition of L-oxiracetam for injection prepared in examples 1-3 has a fixed shape, no bottle spraying phenomenon exists in the freeze-drying process, the product impurities are less, and all indexes meet the production requirements.
Secondly, insoluble particle investigation:
the lyophilized compositions of levo-oxiracetam for injection prepared in example 2 and comparative example 1 were diluted with 250ml of 0.9% sodium chloride injection and 5% glucose injection, respectively, to prepare intravenous drip solutions, and insoluble microparticles were measured at 0, 4, 8, and 12 hours, respectively, with reference to the first method of insoluble microparticle inspection method (photoresist method) in the fourth part of the chinese pharmacopoeia 2015, and the number of insoluble microparticles in each labeled amount was calculated, and the test results are shown in the following table:
from the results of insoluble microparticle examination, it can be seen that the product stability of example 2 is significantly better than that of comparative example 1, after the solution is dissolved in glucose injection or sodium chloride injection to prepare an intravenous drip solution, the insoluble microparticles of example 2 are significantly less than those of comparative example 1, and as the standing time is prolonged, the insoluble microparticles of example 2 are hardly increased, while the insoluble microparticles of comparative example 1 are significantly increased.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (3)
1. The levo-oxiracetam freeze-dried composition for injection is characterized by comprising the following components in parts by weight: the freeze-dried composition comprises the following raw and auxiliary materials in parts by weight: 50-60% of levo-oxiracetam, 20-25% of L-serine, 10-17% of mannitol, 5-7% of sodium glutamate and 5-10% of sodium bisulfite, in percentage by weight; the preparation method of the levo-oxiracetam freeze-dried composition for injection comprises the following steps:
(1) concentration and preparation: placing the raw and auxiliary materials in a container according to the prescription amount, adding 10 weight-times of sterilized water for injection of levetiracetam, stirring, dissolving, adding 0.1 mass percent of injectable activated carbon, stirring for 30min, filtering with a 0.45-micron microporous filter membrane, and collecting the filtrate for later use;
(2) diluting and preparing: adding sterile injection water into the filtrate to 1000 times of the volume of the filtrate, adjusting the pH value to 3.2-3.6 by using 0.1mol/L hydrochloric acid or 0.1mol/L sodium hydroxide, then performing sterile filtration by using a 0.22 micron microporous filter membrane, filling and subpackaging the qualified filtrate in a sterile glass bottle for later use;
(3) and (3) freeze drying: freeze-drying the liquid medicine in the sterile glass bottle in a freeze dryer;
(4) and (3) rolling a cover: and cleaning the aluminum-plastic combined cover, sterilizing, drying, and rolling to obtain the aluminum-plastic combined cover.
2. The lyophilized composition of levo-oxiracetam for injection according to claim 1, characterized in that: the freeze-dried composition comprises the following raw and auxiliary materials in parts by weight: 53% of levo-oxiracetam, 22% of L-serine, 12% of mannitol, 6% of sodium glutamate and 7% of sodium bisulfite.
3. The method for preparing the lyophilized composition of levooxiracetam for injection according to claim 1 or 2, characterized in that: the method comprises the following steps:
(1) concentration and preparation: placing the raw and auxiliary materials in a container according to the prescription amount, adding 10 weight-times of sterilized water for injection of levetiracetam, stirring, dissolving, adding 0.1 mass percent of injectable activated carbon, stirring for 30min, filtering with a 0.45-micron microporous filter membrane, and collecting the filtrate for later use;
(2) diluting and preparing: adding sterile injection water into the filtrate to 1000 times of the volume of the filtrate, adjusting the pH value to 3.2-3.6 by using 0.1mol/L hydrochloric acid or 0.1mol/L sodium hydroxide, then performing sterile filtration by using a 0.22 micron microporous filter membrane, filling and subpackaging the qualified filtrate in a sterile glass bottle for later use;
(3) and (3) freeze drying: freeze-drying the liquid medicine in the sterile glass bottle in a freeze dryer;
(4) and (3) rolling a cover: and cleaning the aluminum-plastic combined cover, sterilizing, drying, and rolling to obtain the aluminum-plastic combined cover.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993006826A1 (en) * | 1991-10-08 | 1993-04-15 | Smithkline Beecham Farmaceutici S.P.A. | Composition comprising s-oxiracetame for use as nootropic |
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| 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 |
| CN102670497A (en) * | 2012-05-31 | 2012-09-19 | 北京阜康仁生物制药科技有限公司 | Stable S-oxiracetam preparation for injection and preparation method of same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993006826A1 (en) * | 1991-10-08 | 1993-04-15 | Smithkline Beecham Farmaceutici S.P.A. | Composition comprising s-oxiracetame for use as nootropic |
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