CN105213424B

CN105213424B - A kind of preparation method of Mannitol sodium chloride injection

Info

Publication number: CN105213424B
Application number: CN201410317630.1A
Authority: CN
Inventors: 徐世兰; 欧苏; 朱勇; 蔡小平
Original assignee: QINGSHAN LIKANG PHARMACEUTICAL INDUSTRY Co Ltd CHENGDU
Current assignee: Chengdu Qingshan Likang Pharmaceutical Co Ltd
Priority date: 2014-07-04
Filing date: 2014-07-04
Publication date: 2019-01-08
Anticipated expiration: 2034-07-04
Also published as: CN105213424A

Abstract

The present invention provides a kind of preparation methods of Mannitol sodium chloride injection, it is that fructose, glycerol, sodium chloride are dissolved in water for injection to be prepared, unlike the prior art, fructose and sodium chloride are not present in simultaneously in the aqueous solution through high-temperature sterilization, in the Mannitol sodium chloride injection, stabilizer is free of.Present inventors have surprisingly found that under the premise of guaranteeing sterile horizontal, as long as high-temperature sterilization is carried out after sodium chloride not being mixed with fructose simultaneously, it will be able to preferably fructose be avoided to degrade, reduce HMF content, improve safety.

Description

A kind of preparation method of Mannitol sodium chloride injection

Technical field

The present invention relates to a kind of preparation methods of Mannitol sodium chloride injection.

Background technique

Mannitol sodium chloride injection, clinically as drop intracranial pressure drug, securely and reliably.But due to fructose itself It is unstable, have now been found that the amount rapid increase for leading to the 5 hydroxymethyl furfural (HMF) in product after sterilizing and in placement process. HMF has damage to human body striated muscle and internal organ, and has neurotoxicity, and accumulation of poisoning, institute can be generated in conjunction with human body protein Must be controlled in the formulation as a kind of important related substances.

It is provided under " Chinese Pharmacopoeia " 2010 editions two " Mannitol sodium chloride injection " items, HMF is accordingly examined in injection The trap surveyed under wavelength 284nm is no more than 0.30, however most execution standards are no more than 0.8 at present.Therefore, it preferably controls The limitation of HMF processed is the eternal pursuit of each Mannitol sodium chloride injection researcher.

Number of patent application CN201210143332, CN101991589A etc. solve fructose shakiness by the way that stabilizer is added Determine problem.However, injection works rapidly, the addition of more auxiliary materials can more or less bring the hidden danger of safety, stabilizer It is same.If it is possible to reduce HMF content, it will preferably keep away on the basis of not outer plus enhancing stability auxiliary material Exempt from auxiliary material bring security risk.In application number CN201310344690.8, stabilizer is not added, is gone out by more complicated high temperature Bacterium and cooling process can make HMF≤0.6, and still, 0.6 limit is still higher.

Summary of the invention

The purpose of the present invention is to provide a kind of preparing for Mannitol sodium chloride injection without extraneous stabilizing agents is new Method.

Inventor is chanced on by previous experiments, and sodium chloride, in the case where mixing, through high-temperature sterilization, can add with fructose The degradation of fast fructose causes to generate more 5 hydroxymethyl furfurals, but in the case where being not added with sodium chloride, fructose itself is through height Temperature sterilizing is without generation high temperature

The present invention provides a kind of preparation methods of Mannitol sodium chloride injection, it is by fructose, glycerol, sodium chloride It is dissolved in water for injection to be prepared, unlike the prior art, fructose and sodium chloride are not present in simultaneously through high-temperature sterilization In aqueous solution；In the Mannitol sodium chloride injection, stabilizer is free of.

Further, the concrete operations of preparation method of the present invention are as follows:

After taking glycerol and sodium chloride to dissolve, decarbonization filtering is filling, high-temperature sterilization；Again aseptically, fructose is added In solution after to sterilizing, mix to get Mannitol sodium chloride injection.

Further, concrete operations are as follows: taking glycerol and sodium chloride, after adding injection water to 1000ml dissolution, add Heat is added active carbon and handles 15 minutes to 60 DEG C, and decarburization filtering is filling, sterilizes 12 minutes at 121 DEG C；

2), by sterile fructose be added to sterilizing after solution in, dissolution mix to get.

Wherein, in the injection, every 1000ml contains glycerol 100g, fructose 50g, sodium chloride 9g.

Further, the stabilizer is the injection auxiliary material for preventing 5 hydroxymethyl furfural from generating.

Wherein, the stabilizer be EDTA or its salt, citric acid, sodium sulfite, sodium hydrogensulfite, in cysteine hydrochloride A combination of one or more.

Present inventors have surprisingly found that under the premise of guaranteeing sterile horizontal, as long as after sodium chloride not being mixed with fructose High-temperature sterilization is carried out simultaneously, it will be able to preferably fructose be avoided to degrade, be reduced HMF content.

Not extraneous stabilizing agents in the method for the present invention, equally also avoid auxiliary material be added it is hidden to injection bring safety Suffer from.

Specific embodiment

Absorbency detection method of the HMF at 284nm is according to " Chinese Pharmacopoeia " 2010 editions two " glycerol fruits in the present invention It is provided under sugared sodium chloride injection " item.

Embodiment 1

1) after, 100g glycerol and 9g sodium chloride add water to 1000ml dissolution, 60 DEG C are heated to, active carbon is added and handles 15 points Clock, decarburization filtering is filling, sterilizes 12 minutes at 121 DEG C.

2), the sterile fructose of 50g is added in the sample after sterilizing, is mixed to get this product: Glycerin Fructose chloride injection Liquid.

Embodiment 2

1) after, 100g glycerol and 9g sodium chloride add water to 1000ml dissolution, 100 DEG C are heated to, active carbon processing 15 is added Minute, decarburization filtering is filling, sterilizes 15 minutes at 121 DEG C.

By the sample of Examples 1 and 2: number 1#, 2#, with the product according to common process, number 3# carries out quality versus It investigates, measurement result see the table below:

(note: common process: after 100g glycerol, 50g fructose and 9g sodium chloride add water to 1000ml dissolution, being heated to 80 DEG C, Active carbon is added to handle 15 minutes, decarburization filtering is filling, sterilizes 8 minutes at 121 DEG C.)

Table 1

It investigates item (HMF)	1#	2#	3#
				0 day	0.06	0.05	0.28
60 DEG C 5 days	0.08	0.09	0.67
				60 DEG C 10 days	0.18	0.16	1.59
40 DEG C of January	0.07	0.08	0.57
				40 DEG C 2 months	0.11	0.12	0.82
40 DEG C of March	0.17	0.20	1.59
				40 DEG C of June	0.24	0.25	2.77

As seen from the above table: the sample obtained according to the invention patent investigates detection by accelerating, with general configuration sample pair Than as a result the amount of HMF is substantially reduced, and product stability significantly improves.

In addition, more at present patented method and technical literature, are difficult to the HMF in Mannitol sodium chloride injection Absorbance is reduced within 0.3, however, the method for the present invention but can achieve standards of pharmacopoeia, product quality is obviously improved, and is improved The safety of clinical application.

The present invention is in early period it was unexpectedly observed that high-temperature sterilization, the degradation to fructose after sodium chloride is separated, mixed with fructose It has a significant impact, concrete analysis process is as follows:

Prepare glycerin and fructose injection: number 1# (not sodium chloride-containing).It prepares Mannitol sodium chloride injection: compiling Number 2#.EDTA-2Na is added in 2# sample solution: number 3#；Purpose be investigate have sodium chloride under conditions of, product HMF's It generates and by the effect after EDTA-2Na, as a result see the table below:

Table 2

Condition	1#	2#	3#
				Before sterilizing	0.03	0.03	0.03
121 DEG C, 8 minutes	0.08	0.23	0.07
				60 DEG C, 5 days	0.19	1.13	0.16
60 DEG C, 10 days	0.48	1.65	0.46

By upper table data it can be seen that

The glycerin and fructose injection for not adding sodium chloride, after high-temperature sterilization, accelerated test, HMF is complied with standard Mannitol sodium chloride injection after (1#), with addition stabilizer EDTA-2Na is quite (3#)；Glycerol fruit containing sodium chloride Sugared sodium chloride injection, after high-temperature sterilization, accelerated test, HMF is dramatically increased, and has exceeded limit standard (2#).

In conjunction with table 1,2 it can be seen that

(1) when not containing sodium chloride in injection, even if fructose is by high-temperature sterilization and accelerated test, HMF value is all still It so complies with standard, i.e., high temperature is not the principal element that HMF is exceeded in Mannitol sodium chloride injection.

(2) it when containing fructose and sodium chloride simultaneously in injection, is handled by high-temperature sterilization, fructose will be accelerated to degrade For HMF.After sodium chloride and glycerol mixing high-temperature sterilization, fructose is added, although fructose and sodium chloride are also at admixture, However, gained injection HMF in accelerated test is still up to standard, good stability ensure that.

As long as the above analysis can be seen that fructose and sodium chloride are not mixed after by high-temperature sterilization, it will be able to have Effect avoids fructose from degrading.Therefore, it in such a way that fructose and sodium chloride are separated high-temperature sterilization or sterile working, can effectively drop Low HMF content, improves the safety of injection.

Claims

1. a kind of preparation method of Mannitol sodium chloride injection, it is that fructose, glycerol, sodium chloride are dissolved in water for injection system It is standby to form, it is characterised in that: in the Mannitol sodium chloride injection, to be free of stabilizer；

Wherein, the concrete operations of the preparation method are as follows:

After taking glycerol and sodium chloride to dissolve, decarbonization filtering is filling, high-temperature sterilization；Again aseptically, sterile fructose is added In solution after to sterilizing, mix to get Mannitol sodium chloride injection.

2. preparation method according to claim 1, it is characterised in that: concrete operations are as follows:

1) glycerol and sodium chloride, are taken, after adding injection water to 1000ml dissolution, is heated to 60 DEG C, active carbon processing 15 is added Minute, decarburization filtering is filling, sterilizes 12 minutes at 121 DEG C；

2), aseptically, by sterile fructose be added to sterilizing after solution in, dissolution mix to get.

3. preparation method according to any one of claims 1 or 2, it is characterised in that: in the injection, every 1000ml Contain glycerol 100g, fructose 50g, sodium chloride 9g.

4. preparation method according to claim 1, it is characterised in that: the stabilizer is that 5 hydroxymethyl furfural is prevented to generate Injection auxiliary material.

5. the preparation method according to claim 4, it is characterised in that: the stabilizer is EDTA or its salt, citric acid, Asia The combination of one or more of sodium sulphate, sodium hydrogensulfite, cysteine hydrochloride.