CN107303266B - Levo-oxiracetam injection and preparation method thereof - Google Patents
Levo-oxiracetam injection and preparation method thereof Download PDFInfo
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- CN107303266B CN107303266B CN201610238973.8A CN201610238973A CN107303266B CN 107303266 B CN107303266 B CN 107303266B CN 201610238973 A CN201610238973 A CN 201610238973A CN 107303266 B CN107303266 B CN 107303266B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- 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 injection and a preparation method thereof; each mL of injection contains the following raw and auxiliary materials: 180-220mg of levo-oxiracetam, 0.01-0.1mg of edetate disodium, 4-5mg of methylparaben and 10-16mg of meglumine; the preparation method of the injection comprises the steps of concentration, dilution, filling, sterilization and the like. The prepared levo-oxiracetam injection does not foam, does not have the problem of liquid medicine adhesion, has high product yield, good product stability, long validity period and few product impurities by utilizing the defoaming effect of methyl hydroxybenzoate and the dissolving-assisting stabilizing effect of disodium edetate and meglumine, and all indexes meet the production requirements.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a levo-oxiracetam 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.
The existing levo-oxiracetam injection is easy to generate foam in the filling process, an ampoule bottle is adopted for filling, the liquid medicine is adhered to the bottle opening, the liquid medicine is carbonized in the ampoule bottle sealing process, so that visible foreign matters of a product are unqualified, the product yield is reduced, and the unknown safety of the patient in medicine use is increased; the penicillin bottle is adopted for filling, the solution is adhered to the bottle mouth, the plug is easy to jump, and the product yield is also reduced.
Disclosure of Invention
In view of the above, the invention aims to provide a levo-oxiracetam injection and a preparation method thereof, wherein the injection does not foam, does not have the problem of adhesion of the injection, and improves the product yield.
In order to achieve the purpose, the invention provides the following technical scheme:
a levo-oxiracetam injection contains the following raw and auxiliary materials in each mL of injection: 180-220mg of levo-oxiracetam, 0.01-0.1mg of edetate disodium, 4-5mg of methylparaben and 10-16mg of meglumine.
Furthermore, each mL of the injection contains the following raw and auxiliary materials: 200mg of levo-oxiracetam, 0.05mg of edetate disodium, 4.5mg of methylparaben and 13mg of meglumine.
The preparation method of the levo-oxiracetam injection comprises the following steps:
(1) concentration and preparation: weighing methylparaben and meglumine according to the prescription amount, adding the methylparaben and the meglumine into water for injection, stirring and dissolving, adjusting the pH value to 6.0 by using 0.1mol/L hydrochloric acid solution, adding edetate disodium and levooxiracetam according to the prescription amount, stirring and dissolving, and adjusting the pH value to 5.0 by using 0.1mol/L hydrochloric acid solution to obtain concentrated solution;
(2) diluting and preparing: taking the concentrated solution, diluting to constant volume with water for injection, filtering with 0.45 μm filter membrane, and collecting filtrate;
(3) filling: after the inspection is qualified, filling the liquid medicine in a production line, wherein the horizontal height of the position of the buffer liquid storage tank is 10-15 cm higher than that of the position of the liquid medicine nozzle during filling;
(4) and (3) sterilization: and (3) feeding the filled semi-finished product of the anzaiton into a steam sterilization pot for sterilization to obtain the levo-oxiracetam injection.
Further, nitrogen is required to be introduced for treatment in the concentration process in the step (1), and the nitrogen flow is 0.03-0.08L/min; and (3) in the filling process of the step (3), the buffer liquid storage tank needs to be filled with nitrogen, and the filling process needs to be filled with nitrogen with the purity of 99.99% so that the oxygen content in the water for injection in the tank does not exceed 0.01%.
The invention has the beneficial effects that:
the prepared levo-oxiracetam injection does not foam, does not have the problem of liquid medicine adhesion, has high product yield, good product stability, long validity period and few product impurities by utilizing the defoaming effect of methyl hydroxybenzoate and the dissolving-assisting stabilizing effect of disodium edetate and meglumine, and all indexes meet the production requirements.
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 formula of the levo-oxiracetam injection of example 1 is shown in the following table:
the preparation method of the levo-oxiracetam injection of embodiment 1 comprises the following steps:
(1) concentration and preparation: weighing methylparaben and meglumine according to the prescription amount, adding the methylparaben and the meglumine into water for injection, stirring and dissolving, adjusting the pH value to 6.0 by using 0.1mol/L hydrochloric acid solution, adding edetate disodium and levooxiracetam according to the prescription amount, stirring and dissolving, and adjusting the pH value to 5.0 by using 0.1mol/L hydrochloric acid solution to obtain concentrated solution; nitrogen is introduced for treatment in the concentration process, and the flow rate of the nitrogen is 0.03-0.08L/min;
(2) diluting and preparing: taking the concentrated solution, diluting to 1000mL with water for injection, filtering with 0.45 μm filter membrane, and collecting filtrate;
(3) filling: after the inspection is qualified, filling the liquid medicine in a production line, wherein the horizontal height of the position of the buffer liquid storage tank is 10-15 cm higher than that of the position of the liquid medicine nozzle during filling; in the filling process, the buffer liquid storage tank needs to be filled with nitrogen, and the filling process needs to be filled with nitrogen with the purity of 99.99 percent so that the oxygen content in the water for injection in the tank does not exceed 0.01 percent;
(4) and (3) sterilization: and (3) feeding the filled Ancui semi-finished product into a steam sterilization pot for sterilization, and sterilizing at 121 ℃ for 15min to obtain the levo-oxiracetam injection.
Comparative example 1
The levo-oxiracetam injection of comparative example 1 was prepared without adding methylparaben, and the remaining components and preparation method were the same as those of example 1.
Example 2
The formula of the levo-oxiracetam injection of example 2 is shown in the following table:
the preparation method of the levo-oxiracetam injection of the embodiment 2 is the same as that of the embodiment 1.
Comparative example 2
The levo-oxiracetam injection of comparative example 2 was prepared without adding methylparaben, and the remaining components and preparation method were the same as in example 2.
Example 3
The formula of the levo-oxiracetam injection of example 3 is shown in the following table:
the preparation method of the levo-oxiracetam injection of the embodiment 3 is the same as that of the embodiment 1.
Comparative example 3
The levo-oxiracetam injection of comparative example 3 was prepared without adding methylparaben, and the remaining components and preparation method were the same as those of example 3.
Firstly, long-term test investigation:
the levo-oxiracetam injection prepared in the embodiment 1-3 is packaged on the market, placed in a long-term sample-holding box, sampled for a certain time and inspected on an investigation item.
Long-term test temperature: 20 ± 2 ℃, humidity: RH 60% ± 10%, investigation time: 0. 12 and 24 months, and the indexes are considered: appearance, visible foreign matter, pH, related substances, and content.
Long-term test stability recording:
according to the long-term test investigation results, the levo-oxiracetam injection prepared in the embodiment 1-3 has the advantages of good product stability, long validity period and few product impurities, and all indexes meet the production requirements.
Secondly, calculating the yield:
the product yields of examples 1 to 3 and comparative examples 1 to 3 were calculated as follows:
| example 1 | Example 2 | Example 3 | Comparative example 1 | Comparative example 2 | Comparative example 3 | |
| Theoretical yield (bottle) | 200 | 200 | 200 | 200 | 200 | 200 |
| Actual production (bottle) | 172 | 165 | 170 | 134 | 130 | 125 |
| Yield (%) | 86 | 82.5 | 85 | 67 | 65 | 62.5 |
According to the calculation result of the yield, the liquid medicine adhered to the bottle mouth is carbonized to cause that the visible foreign matters of the injection are unqualified when the ampoule bottle is sealed by melting at high temperature because the liquid medicine is adhered to the bottle mouth of the ampoule bottle in the filling process of the comparative example, so that the product yield is reduced; in the embodiment, the liquid medicine does not foam, so that the situation of adhering the opening of the ampoule is avoided, and the yield is greatly improved.
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. A levo-oxiracetam injection is characterized in that: each mL of injection contains the following raw and auxiliary materials: 220mg of levo-oxiracetam 180-containing material, 0.01-0.1mg of edetate disodium, 4-5mg of methylparaben and 10-16mg of meglumine;
the preparation method of the levo-oxiracetam injection comprises the following steps:
(1) concentration and preparation: weighing methylparaben and meglumine according to the prescription amount, adding the methylparaben and the meglumine into water for injection, stirring and dissolving, adjusting the pH value to 6.0 by using 0.1mol/L hydrochloric acid solution, adding edetate disodium and levooxiracetam according to the prescription amount, stirring and dissolving, and adjusting the pH value to 5.0 by using 0.1mol/L hydrochloric acid solution to obtain concentrated solution;
(2) diluting and preparing: taking the concentrated solution, diluting to constant volume with water for injection, filtering with 0.45 μm filter membrane, and collecting filtrate;
(3) filling: after the inspection is qualified, filling the liquid medicine in a production line, wherein the horizontal height of the position of the buffer liquid storage tank is 10-15 cm higher than that of the position of the liquid medicine nozzle during filling;
(4) and (3) sterilization: and (4) feeding the filled ampoule semi-finished product into a steam sterilization pot for sterilization to obtain the levo-oxiracetam injection.
2. The levo-oxiracetam injection according to claim 1, characterized in that: each mL of injection contains the following raw and auxiliary materials: 200mg of levo-oxiracetam, 0.05mg of edetate disodium, 4.5mg of methylparaben and 13mg of meglumine.
3. The levo-oxiracetam injection according to claim 1 or 2, characterized in that: the concentration preparation process in the step (1) needs nitrogen introduction treatment, and the nitrogen flow is 0.03-0.08L/min; and (3) in the filling process of the step (3), the buffer liquid storage tank needs to be filled with nitrogen, and the filling process needs to be filled with nitrogen with the purity of 99.99% so that the oxygen content in the water for injection in the tank does not exceed 0.01%.
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| CN201610238973.8A CN107303266B (en) | 2016-04-18 | 2016-04-18 | Levo-oxiracetam injection and preparation method thereof |
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| CN201610238973.8A CN107303266B (en) | 2016-04-18 | 2016-04-18 | Levo-oxiracetam injection and preparation method thereof |
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| CN107303266B true CN107303266B (en) | 2020-09-08 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101217939A (en) * | 2005-05-27 | 2008-07-09 | 灵药生物技术有限公司 | Injectable compositions and process of preparation thereof |
| KR20090098325A (en) * | 2008-03-14 | 2009-09-17 | 엔자이텍 주식회사 | Process for preparing racemic or optically pure (s)-oxiracetam |
| CN101766565A (en) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | Oral liquid preparation with levo-oxiracetam as active component |
| 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 |
| CN102512363A (en) * | 2011-12-23 | 2012-06-27 | 重庆药友制药有限责任公司 | Oxiracetam injection and preparation method thereof |
| CN102525899A (en) * | 2012-01-17 | 2012-07-04 | 山东罗欣药业股份有限公司 | Injection solution of oxiracetam composition and preparation method thereof |
-
2016
- 2016-04-18 CN CN201610238973.8A patent/CN107303266B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101217939A (en) * | 2005-05-27 | 2008-07-09 | 灵药生物技术有限公司 | Injectable compositions and process of preparation thereof |
| KR20090098325A (en) * | 2008-03-14 | 2009-09-17 | 엔자이텍 주식회사 | Process for preparing racemic or optically pure (s)-oxiracetam |
| CN101766565A (en) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | Oral liquid preparation with levo-oxiracetam as active component |
| 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 |
| CN102512363A (en) * | 2011-12-23 | 2012-06-27 | 重庆药友制药有限责任公司 | Oxiracetam injection and preparation method thereof |
| CN102525899A (en) * | 2012-01-17 | 2012-07-04 | 山东罗欣药业股份有限公司 | Injection solution of oxiracetam composition and preparation method thereof |
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