CN101890182B - Preparation method of medical hyaluronic acid gel preparation for sterilizing high-pressure steam - Google Patents
Preparation method of medical hyaluronic acid gel preparation for sterilizing high-pressure steam Download PDFInfo
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Abstract
The invention relates to a preparation method of medical hyaluronic acid gel preparation for sterilizing high-pressure steam, which comprises the steps of: according to the specified requirement, firstly preparing hyaluronic acid gel, and respectively filling the gel into a prefilled syringe by sterile processing technique; then, rapidly heating and cooling; sterilizing for 10min in a high-pressure steam sterilization cabinet under the condition of 110-130 DEG C; and controlling the standard sterilization time F0 of the whole sterilization process not to be less than 8. The preparation method has the advantage that on the premise of ensuring the sterile guarantee value of a moist heat sterilization method not to be less than 6, the medical sodium hyaluronate gel preparation guarantees the product not to have larger thermal degradation, thus reaching the requirements of clinical application.
Description
Technical field
The present invention relates to a kind of preparation method of hyaluronic acid preparation of quick cooling high pressure steam sterilization, the aseptic guarantee value of Medical sodium hyaluronate gel product for preparing by this invention is not less than under 6 the condition, can guarantee that product does not have larger thermal degradation occurs, can reach the requirement of clinical practice.
Background technology
Hyaluronic acid is a kind of linear polysaccharide that alternately is formed by connecting with glycosidic linkage by glucuronic acid and 2-Acetamido-2-deoxy-D-glucose, and its molecular weight is in millions of levels.In the rarer solution of concentration, hyaluronan molecule curls into arbitrarily highly viscoelastic transparent colloid; Under high concentration, stronger film property is arranged.Under physiological condition, the hydroxyl on the alditol acidic group in the hyaluronan molecule is free state, and when after sodium ion is combined, this polysaccharide just is sodium-salt form, is referred to as hyaluronate sodium.
Hyaluronic acid derivatives is at orthopaedics, ophthalmology or at aspects such as composites very large application is arranged all.Because hyaluronic acid is easily degraded at high temperature, therefore in the production of general hyaluronic acid raw material and gel, all be by aseptic filtration and the aseptic aseptic condition of controlling final products of process, the aseptic level value of the product by process control is not less than 3.The present invention has used the cooling sterilizing cabinet that is rapidly heated the Medical sodium hyaluronate gel product has been carried out high pressure steam sterilization, high pressure steam sterilization 10min at 110～130 ℃, the standard sterilization time F0 of whole sterilizing program is not less than 8, the aseptic level value of the product that finally obtains is not less than 6, greatly reduce the Medical sodium hyaluronate gel product as the aseptic risk of implanted aseptic medical product, can guarantee simultaneously that product does not have larger thermal degradation occurs, can reach the requirement of clinical practice.
Summary of the invention
A kind of preparation technology of medical hyaluronic acid gel preparation of high pressure steam sterilization, it is characterized in that, carry out aseptic filtration at the filter element of sodium hyaluronate by 0.45 μ m, behind alcohol precipitation and the vacuum drying, be mixed with gel with physiological buffer, after adopting sterile-processed technique to be divided in the pre-encapsulated injector, use the cooling high pressure steam sterilization cabinet that is rapidly heated to sterilize
Its step is divided into:
The first step: hyaluronate sodium sterile dry preparation
Getting the extraction of bacterial fermentation method and purified molecular weight is dissolved in the water for injection according to 0.1-0.2% concentration greater than 3,000,000 daltonian sodium hyaluronate raw materials, then under the sterile-processed condition, carry out aseptic filtration with 0.45 μ m politef filter element, the sodium chloride solution that adds a certain amount of aseptic filtration after the mixing, adds 95% ethanol that 2.5-3 doubly measures volume, be settled out sodium hyaluronate, and collect, loosen and vacuum drying preparation sodium hyaluronate sterile dry.
Second step: Medical sodium hyaluronate gel preparation
The preparation of buffer: under the sterile-processed condition, according to sodium chloride content 8.0～9.0 ‰, sodium hydrogen phosphate content 1.0～2.0 ‰, the ratio of biphosphate sodium content 0.1～0.2 ‰ takes by weighing above-mentioned article and is dissolved in the water for injection, then adopts the politef filter element of 0.22 μ m to carry out aseptic filtration.
Gel preparation: under the sterile-processed condition, sodium hyaluronate is formulated in the buffer of above-mentioned aseptic filtration sealing according to 15～30mg/ml concentration.
The 3rd step: dissolving
With the gelling vessel of preparation as on the three-dimensional bottle swingging machine, whenever give half an hour shaking flask once, each 15min, shaking flask 3 ~ 5 days leaves standstill after the taking-up, every day, manual shaking flask was 1 time, dissolved fully to sodium hyaluronate.
The 4th step: packing
Under the sterile-processed condition, will dissolving good gel products filters by nitrogen pressurization and 5-8 μ m filter as in the fill tank, adopt the German Gao Ningge fully automatic vacuum filling machine of jumping a queue to be distributed in the prefilled syringe, and vacuum is jumped a queue.
The 5th step: high pressure steam sterilization
The syringe that minute installs product is hung on the special-purpose sterilizing frame, placing the cooling sterilizing cabinet that is rapidly heated to carry out high pressure steam sterilization, the temperature of sterilization is at 110 ~ 130 ℃, and the time is 10min.
The 6th step: aseptic packaging
Gel products after the sterilization is placed bubble-cap, and the above carries out heat seal with special strong defensive QI paper.
Advantage of the present invention has:
1. adopt the high pressure steam sterilization mode that the Medical sodium hyaluronate gel formulation products is carried out terminal sterilization, adopting the aseptic level value of aseptic filtration and process sterile-processed technique to be not less than 3 present domestic Medical sodium hyaluronate gel brings up to and is not less than 6, greatly reduce aseptic Medical sodium hyaluronate gel preparation as the aseptic risk of aseptic implantable medical devices.
2. adopt the cooling sterilizing cabinet that is rapidly heated that the Medical sodium hyaluronate gel preparation is sterilized, whole sterilization time relates to can be controlled in the 20min from being warmed up to be cooled under 60 ℃, greatly reduce the time that present conventional sterilizing cabinet heats up and lowers the temperature, thereby greatly shortened the time of Medical sodium hyaluronate gel product under hot environment, reduced the thermal degradation of this class thermal instability product of Medical sodium hyaluronate gel.
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment.
Embodiment 1
The first step: hyaluronate sodium sterile dry preparation
Getting the extraction of bacterial fermentation method and purified molecular weight is dissolved in the water for injection according to 0.15%% concentration greater than 3,000,000 daltonian sodium hyaluronate raw materials, then under the sterile-processed condition, carry out aseptic filtration with 0.45 μ m politef filter element, the sodium chloride solution that adds a certain amount of aseptic filtration after the mixing, adds 95% ethanol that 2.5-3 doubly measures volume, be settled out sodium hyaluronate, and collect, loosen and vacuum drying preparation sodium hyaluronate sterile dry.
Second step: Medical sodium hyaluronate gel preparation
The preparation of buffer: under the sterile-processed condition, take by weighing sodium chloride content 8.5g, sodium hydrogen phosphate 1.3g, sodium dihydrogen phosphate 0.12g is dissolved in the 1000ml water for injection, then adopts the politef filter element of 0.22 μ m to carry out aseptic filtration.
Gel preparation: under the sterile-processed condition, take by weighing in the buffer of the above-mentioned aseptic filtration of 15g sodium hyaluronate sterile dry adding sealing.
The 3rd step: dissolving
With the gelling vessel of preparation as on the three-dimensional bottle swingging machine, every half an hour shaking flask once, each 15min, shaking flask 3 ~ 5 days leaves standstill after the taking-up, every day, manual shaking flask was 1 time, totally 10 days.
The 4th step: packing
Under the sterile-processed condition, will dissolving good gel products filters by nitrogen pressurization and 5-8 μ m filter as in the fill tank, adopts the German Gao Ningge fully automatic vacuum filling machine of jumping a queue to be distributed in the 2.25ml prefilled syringe, packing specification 1ml, and vacuum is jumped a queue.
The 5th step: high pressure steam sterilization
The syringe that minute installs product is hung on the special-purpose sterilizing frame, placing the cooling sterilizing cabinet that is rapidly heated to carry out high pressure steam sterilization, the temperature of sterilization is at 110 ~ 130 ℃, and sterilization time is 10min.
The 6th step: aseptic packaging
Gel products after the sterilization is placed bubble-cap, and the above carries out heat seal with special strong defensive QI paper.
Embodiment 2
The first step: with embodiment 1.
Second step: Medical sodium hyaluronate gel preparation
The preparation of buffer: under the sterile-processed condition, take by weighing sodium chloride content 8.5g, sodium hydrogen phosphate 1.5g, sodium dihydrogen phosphate 0.15g is dissolved in the 1000ml water for injection, then adopts the politef filter element of 0.22 μ m to carry out aseptic filtration.
Gel preparation: under the sterile-processed condition, take by weighing in the buffer of the above-mentioned aseptic filtration of 20g sodium hyaluronate sterile dry adding sealing.
The ~ the six step of the 3rd step: with example 1.
Embodiment 3
The first step: with embodiment 1.
Second step: Medical sodium hyaluronate gel preparation
The preparation of buffer: under the sterile-processed condition, take by weighing sodium chloride content 8.2g, sodium hydrogen phosphate 1.3g, sodium dihydrogen phosphate 0.13g is dissolved in the 1000ml water for injection, then adopts the politef filter element of 0.22 μ m to carry out aseptic filtration.
Gel preparation: under the sterile-processed condition, take by weighing in the buffer of the above-mentioned aseptic filtration of 25g sodium hyaluronate sterile dry adding sealing.
The ~ the six step of the 3rd step: with embodiment 1.
Embodiment 4
The first step: with implementing 1.
Second step: Medical sodium hyaluronate gel preparation
The preparation of buffer: under the sterile-processed condition, take by weighing sodium chloride 8.0g, sodium hydrogen phosphate 1.1g, sodium dihydrogen phosphate 0.11g is dissolved in the 1000ml water for injection, then adopts the politef filter element of 0.22 μ m to carry out aseptic filtration.
Gel preparation: under the sterile-processed condition, take by weighing in the buffer of the above-mentioned aseptic filtration of 30g sodium hyaluronate sterile dry adding sealing.
The ~ the six step of the 3rd step: with embodiment 1.
Below be that the product of each example sterilization front and back and the main performance of the Medical sodium hyaluronate gel formulation products of present process aseptic controlling compare.
Claims (1)
1. the preparation technology of the medical hyaluronic acid gel preparation of a high pressure steam sterilization, it is characterized in that, carry out aseptic filtration at the filter element of sodium hyaluronate by 0.45 μ m, behind alcohol precipitation and the vacuum drying, be mixed with gel with physiological buffer, after adopting sterile-processed technique to be divided in the pre-encapsulated injector, use the cooling high pressure steam sterilization cabinet that is rapidly heated to sterilize, its step is divided into:
1. hyaluronate sodium sterile dry preparation
Getting the extraction of bacterial fermentation method and purified molecular weight is dissolved in the water for injection according to 0.1～0.2% concentration greater than 3,000,000 daltonian sodium hyaluronate raw materials, then under the sterile-processed condition, carry out aseptic filtration with 0.45 μ m politef filter element, the sodium chloride solution that adds a certain amount of aseptic filtration after the mixing, adds 95% ethanol of 2.5～3 times of amount volumes, be settled out sodium hyaluronate, and collect, loosen and vacuum drying preparation sodium hyaluronate sterile dry;
2. Medical sodium hyaluronate gel preparation
The preparation of buffer: under the sterile-processed condition, according to sodium chloride content 8.0～9.0 ‰, sodium hydrogen phosphate content 1.0～2.0 ‰, the ratio of biphosphate sodium content 0.1～0.2 ‰ takes by weighing above-mentioned article and is dissolved in the water for injection, then adopts the politef filter element of 0.22 μ m to carry out aseptic filtration;
Gel preparation: under the sterile-processed condition, sodium hyaluronate is formulated in the buffer of above-mentioned own aseptic filtration sealing according to 15～30mg/ml concentration;
The 3rd step: dissolving
The gelling vessel of preparation is placed on the three-dimensional bottle swingging machine, every half an hour shaking flask once, each 15min, shaking flask 3～5 days leaves standstill after the taking-up, every day, manual shaking flask was 1 time, dissolved fully to sodium hyaluronate;
The 4th step: packing
Under the sterile-processed condition, the gel products that dissolving is good places the fill tank, filters by nitrogen pressurization and 5-8 μ m filter, adopt the German Gao Ningge fully automatic vacuum filling machine of jumping a queue to be distributed in the pre-encapsulated injector, and vacuum is jumped a queue; The 5th step: high pressure steam sterilization
The syringe that minute installs product is hung on the special-purpose sterilizing frame, placing the cooling sterilizing cabinet that is rapidly heated to carry out high pressure steam sterilization, the temperature of sterilization is at 110～130 ℃, and the time is 10min;
The 6th step: aseptic packaging
Gel products after the sterilization is placed bubble-cap, and the above carries out heat seal with special strong defensive QI paper.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2484387A1 (en) | 2011-02-03 | 2012-08-08 | Q-Med AB | Hyaluronic acid composition |
| CN102488911A (en) * | 2011-11-29 | 2012-06-13 | 上海景峰制药有限公司 | Sodium hyaluronate injection sterilization method for guaranteeing aseptic packaging |
| CN103254448B (en) * | 2013-05-17 | 2015-06-24 | 成都金凯生物技术有限公司 | Medical sodium hyaluronate gel and preparation method thereof |
| CN106139258B (en) * | 2015-04-08 | 2019-03-26 | 上海昊海生物科技股份有限公司 | A kind of method that pipeline prepares sterile Medical sodium hyaluronate gel |
| CN106139178A (en) * | 2015-04-24 | 2016-11-23 | 上海建华精细生物制品有限公司 | A kind of sterilizing methods of hyaluronic acid sodium gel |
| CN105461825B (en) * | 2015-12-24 | 2017-12-29 | 浙江景嘉医疗科技有限公司 | A kind of method for improving sodium hyaluronate highly finished product recovery rate |
| CN107029282A (en) * | 2016-02-03 | 2017-08-11 | 惠众国际医疗器械（北京）有限公司 | A kind of Thermo-sensitive medical chitosan derivative formulations and preparation method thereof |
| CN106421842B (en) * | 2016-11-18 | 2019-02-12 | 四川南格尔生物科技有限公司 | One kind removing white filter sterilization process |
| CN115258239B (en) * | 2022-08-01 | 2024-02-27 | 北京中泰邦医药科技有限公司 | Product package for sterile gel medicine and preparation process thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101264348A (en) * | 2008-05-19 | 2008-09-17 | 山东凯乐普生物工程有限公司 | Preparation technique of sodium hyaluronate gel granule |
| CN101502676A (en) * | 2008-02-04 | 2009-08-12 | 山东省药学科学院 | Polymethyl methacryate and crosslinking hyaluronic acid mixed gel for injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101502676A (en) * | 2008-02-04 | 2009-08-12 | 山东省药学科学院 | Polymethyl methacryate and crosslinking hyaluronic acid mixed gel for injection and preparation method thereof |
| CN101264348A (en) * | 2008-05-19 | 2008-09-17 | 山东凯乐普生物工程有限公司 | Preparation technique of sodium hyaluronate gel granule |
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