CN115671044A - Netilmicin sulfate injection and preparation method thereof - Google Patents
Netilmicin sulfate injection and preparation method thereof Download PDFInfo
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- CN115671044A CN115671044A CN202211510108.6A CN202211510108A CN115671044A CN 115671044 A CN115671044 A CN 115671044A CN 202211510108 A CN202211510108 A CN 202211510108A CN 115671044 A CN115671044 A CN 115671044A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a netilmicin sulfate injection and a preparation method thereof; each 1ml of netilmicin sulfate injection comprises: 140-152 mg of netilmicin sulfate, 1.48-1.6 mg of anhydrous sodium sulfite, 0.1-0.3 mg of edetate disodium, 1.5-1.8 mg of sodium metabisulfite, 9-10 mg of benzyl alcohol and water for injection. The preparation method of the injection comprises the following steps: adding edetate disodium, benzyl alcohol, sodium metabisulfite, anhydrous sodium sulfite and netilmicin sulfate into water for injection, and stirring for dissolving; adjusting the pH of the liquid medicine; and (3) sterilizing and filtering the liquid medicine with constant volume, feeding the liquid medicine into a filling and sealing room, sterilizing and filtering again, filling the liquid medicine into an ampoule bottle, filling nitrogen, sealing, and detecting leakage to obtain the product. The injection has the advantages of good stability and no discoloration; the preparation method combines sterilization filtration and aseptic operation, and successfully solves the problem of easy discoloration of injection.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a netilmicin sulfate injection and a preparation method thereof.
Background
Netilmicin Sulfate (NTM) is a new generation of semisynthetic aminoglycoside antibiotics, has hygroscopicity, and has the following chemical structural formula:
netilmicin sulfate has wide antibacterial effect, mainly aims at gram-negative bacilli and a few gram-positive bacilli, and has antibacterial activity on most strains with drug resistance to aminoglycoside antibiotics. The otonephrotoxicity of the medicine is less than that of the similar medicines, the tolerance is good, and the medicine becomes the first choice medicine with clinical application indications of aminoglycosides due to the safety and effectiveness.
At present, netilmicin sulfate has been prepared into various pharmaceutical dosage forms for clinical treatment, mainly including three dosage forms, namely netilmicin sulfate injection, netilmicin sulfate for injection and netilmicin sulfate eye drops. However, netilmicin sulfate is easily soluble in water, is unstable to heat and light, has unsaturated double bonds in the structure, can turn yellow due to oxidation after being exposed in air for a long time, and often has the phenomena of oxidation discoloration, related substance increase and the like in different degrees in the production and storage processes, thereby influencing the quality of netilmicin sulfate products for injection.
According to the experimental results and the reports of relevant documents, the main factors influencing the quality of the injection are as follows: the sterilization temperature, the oxygen in the air and the pH value of the liquid medicine are not easy to exceed 105 ℃, otherwise, the content is reduced, the color is changed into yellow, and related substances are obviously increased. This means that the injection of the product is not easy to be produced by terminal sterilization. So aiming at the existing dosage forms: small-volume injection and large-volume injection, the conventional production method (sterilization at 100 ℃) can not fully ensure the sterility requirement, and particularly the risk of large-volume injection is higher; the freeze-dried powder injection can be aseptically ensured to reach 10 -3 But has the defects of complex preparation process, higher cost, redissolution requirement in clinical use and the like.
Therefore, it would be highly desirable to provide an injection of netilmicin sulfate with excellent pharmaceutical properties, and a method for preparing the injection.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a netilmicin sulfate injection and a preparation method thereof. The netilmicin sulfate injection has the advantages of good stability and difficult color change; the preparation method of the invention adopts a method combining sterilization filtration and aseptic operation, successfully solves the problem that the netilmicin sulfate injection is easy to discolor, and has great application value and economic value.
In order to achieve the technical purpose and achieve the technical effect, the invention is realized by the following technical scheme:
the invention provides a netilmicin sulfate injection, each 1ml of netilmicin sulfate injection comprises: 140-152 mg of netilmicin sulfate, 1.48-1.6 mg of anhydrous sodium sulfite, 0.1-0.3 mg of edetate disodium, 1.5-1.8 mg of sodium metabisulfite, 9-10 mg of benzyl alcohol and water for injection.
Further, the pH of the injection is 5.0-7.0.
Further, the pH of the injection is 5.0 to 5.5.
Further, a pH regulator for regulating the pH of the injection is hydrochloric acid or sodium hydroxide.
The invention further provides a preparation method of the netilmicin sulfate injection, which comprises the following steps:
s1, adding raw materials including edetate disodium, benzyl alcohol, sodium metabisulfite, anhydrous sodium sulfite and netilmicin sulfate into a certain amount of prepared water for injection, and stirring to dissolve the raw materials;
s2, adjusting the pH of the liquid medicine to be within the range of 5.0-7.0 by using a pH regulator, and then adding injection water to full dose;
and S3, sterilizing and filtering the liquid medicine with constant volume, feeding the liquid medicine into a filling and sealing chamber, sterilizing and filtering again, filling the liquid medicine into a cleaned and sterilized ampoule bottle, filling nitrogen, sealing, and detecting leakage to obtain the product.
Furthermore, the water temperature of the water for injection used in the preparation method is below 40 ℃.
Furthermore, the sterilization filtration adopts a 0.45 μm polyethersulfone filter element and a 0.22 μm polyethersulfone liquid sterilization grade filter element.
Further, wherein the nitrogen filling parameters are as follows: the front nitrogen charging flow is more than or equal to 10L/min, and the rear nitrogen charging flow is more than or equal to 5L/min.
The invention has the beneficial effects that:
the netilmicin sulfate injection comprises netilmicin sulfate, anhydrous sodium sulfite, disodium edetate, sodium metabisulfite, benzyl alcohol and water for injection. The invention adopts the cooperation of anhydrous sodium sulfite, sodium metabisulfite and disodium edetate, has synergistic effect, improves the stability of the injection, ensures that the injection is not easy to discolor and ensures the quality of the injection.
The preparation method disclosed by the invention adopts a method combining sterilization filtration and sterile operation, and successfully solves the phenomenon that the netilmicin sulfate injection is easy to discolor by using the polyether sulfone filter core and nitrogen filling matching, so that the preparation method has a great application value and economic value.
Detailed Description
The technical solutions in the present invention will be described clearly and completely with reference to specific embodiments, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
The invention provides a netilmicin sulfate injection, each 1ml of netilmicin sulfate injection comprises: 140-152 mg of netilmicin sulfate, 1.48-1.6 mg of anhydrous sodium sulfite, 0.1-0.3 mg of edetate disodium, 1.5-1.8 mg of sodium metabisulfite, 9-10 mg of benzyl alcohol and water for injection.
Wherein the pH of the injection is 5.0 to 7.0, preferably 5.0 to 5.5.
Wherein, the pH regulator for regulating the pH of the injection is hydrochloric acid or sodium hydroxide.
The invention further provides a preparation method of the netilmicin sulfate injection, which comprises the following steps:
s1, adding edetate disodium, benzyl alcohol, sodium metabisulfite, anhydrous sodium sulfite and netilmicin sulfate raw materials into 60-95% of injection water, and stirring to dissolve;
s2, adjusting the pH of the liquid medicine to be within the range of 5.0-7.0 by using a pH regulator, and then adding injection water to full dose;
and S3, sterilizing and filtering the liquid medicine with constant volume, feeding the liquid medicine into a filling and sealing chamber, sterilizing and filtering again, filling the liquid medicine into a cleaned and sterilized ampoule bottle, filling nitrogen, sealing, and detecting leakage to obtain the product.
Wherein the water temperature of the water for injection used in the preparation method is below 40 ℃.
Wherein the sterilization filtration adopts a 0.45 mu m polyethersulfone filter element and a 0.22 mu m polyethersulfone liquid sterilization grade filter element.
Wherein, the nitrogen filling parameters are as follows: the front nitrogen charging flow is more than or equal to 10L/min, and the rear nitrogen charging flow is more than or equal to 5L/min.
Example 1
1. Prescription
10.606kg of netilmicin sulfate, 7.0g of edetate disodium, 126.0g of sodium metabisulfite, 112.0g of anhydrous sodium sulfite and 700.0g of benzyl alcohol.
Step (ii) of
Adding 70L of water for injection into a preparation tank, wherein the water temperature is 20-30 ℃; agitation was turned on at 60% frequency. And sequentially adding the edetate disodium, sodium metabisulfite, anhydrous sodium sulfite, benzyl alcohol and netilmicin sulfate according to the prescription amount, and stirring until the edetate disodium, the sodium metabisulfite, the anhydrous sodium sulfite, the benzyl alcohol and the netilmicin sulfate are completely dissolved. Adding injection water with the temperature of 20-30 ℃ to a constant volume of 75L, cooling to normal temperature, adjusting the pH value to 5.0-7.0, and stirring the liquid medicine for 10 minutes. Filtering with 0.45 μm polyethersulfone filter element and 0.22 μm polyethersulfone liquid sterilization filter element, subpackaging in ampoule bottle, and capping; filling nitrogen, wherein the front nitrogen filling flow is 12L/min, the rear nitrogen filling flow is 6L/min, and detecting leakage to obtain the product;
stability analysis
1. Test for influencing factor
The netilmicin sulfate injection prepared in example 1 was irradiated at high temperature (50 + -2 deg.C) and light(white light 5500lx, 90 μ w/cm 2 ) Standing for 30 days under the condition, sampling and detecting at 0, 5, 10 and 30 days respectively, and detecting results are shown as follows:
table 1: experimental data of influence factors of netilmicin sulfate injection
2. Accelerated test
The netilmicin sulfate injection prepared in example 1 was placed under accelerated test (40 ℃ ± 2 ℃ and RH75% ± 5%) for 6 months, and sampled and tested at 0, 1, 2, 3 and 6 months, and the test results are as follows:
TABLE 2 acceleration test data for netilmicin sulfate injection
3. Results of low temperature test
The netilmicin sulfate injection prepared in example 1 was subjected to a low temperature test comprising three cycles of 2-8 ℃ for two days, and then examined under an accelerated condition of 40 ℃ for two days.
Table 3: low temperature test data of netilmicin sulfate injection
4. Results of freeze thaw test
The netilmicin sulfate injection prepared in example 1 was subjected to a freeze-thaw test, which included three cycles, each cycle being at-10 to-20 ℃ for two days, and then examined at 40 ℃ for two days under accelerated conditions.
Table 4: freeze-thaw test data of netilmicin sulfate injection
The netilmicin sulfate injection prepared in example 1 was subjected to stability examination, and the data are shown in tables 1-4; it can be seen that the injection of the invention has better stability, the pH value is maintained to be stable, and the netilmicin sulfate is not obviously degraded.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications and equivalents made by the contents of the present invention or directly or indirectly applied to other related technical fields are included in the scope of the present invention.
Claims (8)
1. A netilmicin sulfate injection is characterized in that: each 1ml of netilmicin sulfate injection comprises: 140-152 mg of netilmicin sulfate, 1.48-1.6 mg of anhydrous sodium sulfite, 0.1-0.3 mg of edetate disodium, 1.5-1.8 mg of sodium metabisulfite, 9-10 mg of benzyl alcohol and water for injection.
2. The netilmicin sulfate injection as claimed in claim 1, wherein the pH of the injection is 5.0-7.0.
3. The netilmicin sulfate injection as claimed in claim 2, wherein the pH of the injection is 5.0-5.5.
4. The netilmicin sulfate injection as claimed in claim 1, wherein the pH regulator for adjusting the pH of the injection is hydrochloric acid or sodium hydroxide.
5. A method for preparing the netilmicin sulfate injection as claimed in any one of claims 1 to 4, which comprises the following steps:
s1, adding raw materials of disodium edetate, benzyl alcohol, sodium metabisulfite, anhydrous sodium sulfite and netilmicin sulfate into a certain amount of water for injection, and stirring to dissolve the raw materials;
s2, adjusting the pH of the liquid medicine to be within the range of 5.0-7.0 by using a pH regulator, and then supplementing the water for injection to the full amount;
and S3, sterilizing and filtering the liquid medicine with constant volume, feeding the liquid medicine into a filling and sealing chamber, sterilizing and filtering again, filling the liquid medicine into a cleaned and sterilized ampoule bottle, filling nitrogen, sealing, and detecting leakage to obtain the product.
6. The method of claim 5, wherein the temperature of the water for injection is below 40 ℃.
7. The method for preparing netilmicin sulfate injection as claimed in claim 5, wherein the sterilization filtration adopts 0.45 μm polyethersulfone filter element and 0.22 μm polyethersulfone liquid sterilization grade filter element.
8. The method for preparing netilmicin sulfate injection as claimed in claim 5, wherein the nitrogen filling parameters are: the front nitrogen charging flow is more than or equal to 10L/min, and the rear nitrogen charging flow is more than or equal to 5L/min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202211510108.6A CN115671044A (en) | 2022-11-29 | 2022-11-29 | Netilmicin sulfate injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211510108.6A CN115671044A (en) | 2022-11-29 | 2022-11-29 | Netilmicin sulfate injection and preparation method thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4327087A (en) * | 1978-01-16 | 1982-04-27 | Schering Corporation | Stabilized Netilmicin formulations |
| EP0195114A2 (en) * | 1985-03-07 | 1986-09-24 | CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. | Stabilized injection compositions and their preparations |
| JP2000219621A (en) * | 1999-01-28 | 2000-08-08 | Taiyo Yakuhin Kogyo Kk | Liquid pharmaceutical preparation containing sulfate- containing compound |
| CN102451154A (en) * | 2010-10-14 | 2012-05-16 | 山东方明药业股份有限公司 | Netilmicin sulfate injection and preparation method thereof |
| CN105147599A (en) * | 2015-09-21 | 2015-12-16 | 成都天台山制药有限公司 | Netilmicin sulfate injection and preparing method |
-
2022
- 2022-11-29 CN CN202211510108.6A patent/CN115671044A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4327087A (en) * | 1978-01-16 | 1982-04-27 | Schering Corporation | Stabilized Netilmicin formulations |
| EP0195114A2 (en) * | 1985-03-07 | 1986-09-24 | CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. | Stabilized injection compositions and their preparations |
| JP2000219621A (en) * | 1999-01-28 | 2000-08-08 | Taiyo Yakuhin Kogyo Kk | Liquid pharmaceutical preparation containing sulfate- containing compound |
| CN102451154A (en) * | 2010-10-14 | 2012-05-16 | 山东方明药业股份有限公司 | Netilmicin sulfate injection and preparation method thereof |
| CN105147599A (en) * | 2015-09-21 | 2015-12-16 | 成都天台山制药有限公司 | Netilmicin sulfate injection and preparing method |
Non-Patent Citations (1)
| Title |
|---|
| 李印秋;张丽宝;李冰;黄桂华;: "硫酸奈替米星注射液的处方和工艺对产品质量的影响", 中国药业, no. 02, pages 45 - 46 * |
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