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Freeze-dried powder injection of L-oxiracetam and process for preparing freeze-dried powder injection

A technology for freeze-dried powder injection and excipient, which is applied in the field of freeze-dried powder injection of levoroxiracetam and its preparation technology, can solve the problems of decreased solubility, high solution viscosity, long freeze-drying time, etc., and achieves improved solubility , The effect of increased stability and rapid reconstitution

Active Publication Date: 2013-05-22
南京博德生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Regarding the lyophilized powder injection of oxiracetam, there are CN1486693A, CN102274195A and other literature disclosures: CN1486693A claims that the technical solution recorded in it is well formed in the preparation of the lyophilized powder, and there will be no spray bottle phenomenon. Tests have confirmed that the freeze-dried powder prepared according to this prescription and method is loose in shape and prone to spray bottle phenomenon, and the freeze-drying time is much longer than the description in the examples in the description, up to 50 hours, so it is not suitable for industrial production ; What CN1486693A discloses is the lyophilized powder injection with oxiracetam 0.25 hydrate as main agent, but the preparation process of 0.25 hydrate of oxiracetam is more loaded down with trivial details, and the lyophilized powder stability that makes is not high, also not suitable for for promotion in mass production
[0005] Whether it is oxiracetam or levo-oxiracetam, the viscosity of the solution after it is dissolved in water for injection is very large, and it is difficult to sublimate the water in the process of lyophilization, analysis and drying. There are problems such as long freeze-drying time, increase of related substances, and uneven appearance of freeze-dried finished products
[0006] It is mentioned in CN101396358A that due to its own molecular conformation, there are two situations where the hydroxyl and carbonyl are located on the same side and the opposite side of the pyrrole ring. When the hydroxyl and carbonyl of oxiracetam are located on the same side of the pyrrole ring at the same time, it is easy to The formation of intramolecular hydrogen bonds will reduce the solubility of oxiracetam in water for injection, and white crystalline powder will appear from oxiracetam injection.
Levo-oxiracetam has a similar structure and also has the problem of storage stability. The storage time of the drug solution can be reduced by developing powder injections, but it also has the problem of decreased solubility and cannot be significantly improved by this technical solution.

Method used

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  • Freeze-dried powder injection of L-oxiracetam and process for preparing freeze-dried powder injection
  • Freeze-dried powder injection of L-oxiracetam and process for preparing freeze-dried powder injection
  • Freeze-dried powder injection of L-oxiracetam and process for preparing freeze-dried powder injection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1 prescription 1 and preparation technology

[0032] Prescription 1:

[0033]

[0034]

[0035] Preparation Process:

[0036] 1) Mix 10Kg levoxiracetam and 0.8Kg PEG4000 evenly and disperse them in 35L of hot water at 45-50°C. After the dissolution is complete, add 8kg sorbitol and 0.6kg sodium dihydrogen phosphate to dissolve completely.

[0037] 2) Adjust the pH of the solution to 4.0 with 0.2mol / L disodium hydrogen phosphate solution,

[0038] 3) Add water to full volume, stir for 10 minutes,

[0039] 4) Decarburize 0.1% w / v activated carbon for 15 minutes, filter through a 1 μm titanium rod filter to remove carbon, and filter through a 0.45 μm cartridge filter;

[0040] 5) Sampling after filtration with a 0.22 μm terminal filter for intermediate inspection;

[0041] 6) After passing the inspection, it is potted and sealed in a vial;

[0042] 7) Freeze-drying:

[0043] First put the subpackaged medicines on the inner partition of the freeze-dr...

Embodiment 2

[0046] Embodiment 2 Prescription 2 and preparation process

[0047] Prescription 2:

[0048]

[0049]

[0050] Preparation Process:

[0051] 1) Mix 10kg of levoxiracetam and 0.6kg of PEG6000 evenly and disperse in 40L of hot water at 45-50°C. After the dissolution is complete, add 8k of mannitol and 0.4kg of sodium dihydrogen phosphate to dissolve completely.

[0052] 2) Adjust the pH of the solution to 5.0 with 0.2mol / L disodium hydrogen phosphate solution,

[0053] 3) Add water to full volume, stir for 10 minutes,

[0054] 4) Decarburize 0.1% w / v activated carbon for 15 minutes, filter through a 1 μm titanium rod filter to remove carbon, and filter through a 0.45 μm cartridge filter;

[0055] 5) Sampling after filtration with a 0.22 μm terminal filter for intermediate inspection;

[0056] 6) After passing the inspection, it is potted and sealed in a vial;

[0057] 7) Freeze-drying:

[0058] First put the subpackaged medicines on the inner partition of the freeze-...

Embodiment 3

[0061] Embodiment 3 prescription 3 and preparation process

[0062] Prescription 3:

[0063]

[0064] Preparation Process:

[0065] 1) Mix 10kg of levoxiracetam and 0.8kg of PEG6000 evenly and disperse in 40L of hot water at 45-50°C. After the dissolution is complete, add 10kg of lactose and 0.5kg of sodium dihydrogen phosphate to dissolve completely.

[0066] 2) Adjust the pH of the solution to 5.5 with 0.2mol / L disodium hydrogen phosphate solution,

[0067] 3) Add water to full volume, stir for 10 minutes,

[0068] 4) Decarburize 0.1% w / v activated carbon for 15 minutes, filter through a 1 μm titanium rod filter to remove carbon, and filter through a 0.45 μm cartridge filter;

[0069] 5) Sampling after filtration with a 0.22 μm terminal filter for intermediate inspection;

[0070] 6) After passing the inspection, it is potted and sealed in a vial;

[0071] 7) Freeze-drying:

[0072] First put the subpackaged medicines on the inner partition of the freeze-drying bo...

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Abstract

The invention relates to a freeze-dried powder injection of L-oxiracetam and a process for preparing the freeze-dried powder injection. The freeze-dried powder injection comprises, by weight, 1 part of the L-oxiracetam, 0.1 to 10 parts of an excipient, 0.01 to 1 part of an antisticking agent and 0.01 to 0.5 part of a pH regulator, wherein polyethylene glycol (PEG) series of products serve as the antisticking agent preferably. The freeze-dried powder injection which is prepared on the basis of a prescription according to the process has the advantages of being short in freeze-drying time, attractive in appearance, short in redissolving time and high in stability.

Description

technical field [0001] The invention mainly relates to the technical field of pharmacy, in particular to a freeze-dried powder injection of levoxiracetam and a preparation process thereof. Background technique [0002] Oxiracetam (oxiracetam, CAS No.: 62613-82-5) chemical name is 4-hydroxy-2-oxo-1-pyrrolidineacetamide, which was first synthesized in 1974 by the Italian company ISFS.P.A. Oxygen nootropic drug (compound disclosed in US4118396), is a derivative of cyclic GABOB, which can promote the synthesis of phosphorylcholine and phosphorylethanolamine, promote brain metabolism, pass through the blood-brain barrier, and have a stimulating effect on the specific central nervous system. It can improve intelligence and memory, and also has good curative effect on cerebrovascular disease, traumatic brain injury, brain tumor, intracranial infection, brain degenerative disease, etc., and the drug has extremely low toxicity, no mutagenic, carcinogenic and reproductive toxicity. G...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/19A61K31/4015A61P25/28A61K47/34
Inventor 包玉胜陈乃光柏丹丹曹卫张峰
Owner 南京博德生物制药有限公司
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