CN105213301B - Netilmicin sulfate injection and its quality control method - Google Patents

Netilmicin sulfate injection and its quality control method Download PDF

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CN105213301B
CN105213301B CN201510602716.3A CN201510602716A CN105213301B CN 105213301 B CN105213301 B CN 105213301B CN 201510602716 A CN201510602716 A CN 201510602716A CN 105213301 B CN105213301 B CN 105213301B
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injection
water
netilmicin sulfate
netilmicin
liquid
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CN105213301A (en
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张莲莲
方专
吴国庆
陈娟
余茹
王晓霞
赵东明
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CHENGDU TIANTAISHAN PHARMACEUTICAL CO LTD
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CHENGDU TIANTAISHAN PHARMACEUTICAL Co Ltd
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Abstract

The present invention relates to netilmicin sulfate injection and its quality control methods.Specifically, including in the netilmicin sulfate injection of the present invention:Netilmicin sulfate, sulphite, cysteine, edetate and water for injection.The invention further relates to the preparation methods of the netilmicin sulfate injection, and the method for the detection netilmicin sulfate injection quality index.Netilmicin sulfate injection prepared by the present invention has the excellent properties of at least one aspect as used in the description, and the method that the present invention detects quality index has excellent detection performance.

Description

Netilmicin sulfate injection and its quality control method
Technical field
The invention belongs to technology of pharmaceutical engineering fields, specifically, being related to a kind of netilmicin sulfate product and its matter Prosecutor method, more particularly to a kind of netilmicin sulfate injection and its quality control method.
Background technology
Netilmicin sulfate (Netilmicin Sulfate, NTM) is the semi-synthetic amino sugar of a new generation introduced for 1994 Tobramycin antibiotic is worked by inhibiting the normal protein of sensitive microbial to synthesize.Netilmicin sulfate recorded in 2010 editions and 2015 editions《Chinese Pharmacopoeia》In.The chemical structural formula of netilmicin sulfate, molecular formula and molecular weight are as follows:
Netilmicin sulfate is O-3- deoxidation-4-C- methyl-3- methylaminos-β-L-arabinose pyranose (1->4)-O- [the own pyranose-of 2,6 diamino-2,3,4,6-, four deoxidation-α-D- glyceryl-4- alkene (1->6)] -2- deoxidations-N3Ethyl- L- streptamine sulfate.Its bulk pharmaceutical chemicals is calculated by anhydride, and the potency per 1mg, which must not be less than, is more than 610 Netilmicin units.
Netilmicin sulfate bulk pharmaceutical chemicals are powder or the loose block of white or off-white color;It is odorless, mildly bitter flavor;Have draw it is wet Property.Netilmicin sulfate bulk pharmaceutical chemicals are readily soluble in water, insoluble in ethyl alcohol, chloroform or ether.Its 10mg/ml aqueous solution Specific rotation is+88 ° to+96 °.
The mechanism of action of netilmicin sulfate is combined with bacterial ribosome 30S subunits, and the conjunction of bacterio protein is inhibited At.Suitable for severe infections caused by the sensitive gram-Negative bacillus for the treatment of, such as pseudomonas aeruginosa, Proteus (indoles sun Property and feminine gender), escherichia coli, Klebsiella, Enterobacter, Serratia and citrobacter belong to etc. caused by newborn Pyemia, septicemia, central nervous system infection (including meningitis), urinary tract genital system infection, respiratory tract infection, gastrointestinal tract Infection, peritonitis, infection of biliary tract, skin or bone infection, tympanitis, nasosinusitis, soft tissue infection, listeriosis etc..This Product often can get synergistic effect with beta-lactam class drug combination.
Although listing many cephalosporins and quinolones new drug in recent years, but still can not the unique ammonia of metalepsis mechanism Base glycoside drug.Netilmicin sulfate is that such medicine renal toxicity is slight and more rare, and ototoxicity is mould compared with gentamicin, appropriate cloth Element is low with amikacin, and clinical efficacy is better than gentamicin etc..Become and clinically control because it has more safety and validity Treat the choice drug that sensitive gram-Negative bacillus includes severe infections caused by Pseudomonas aeruginosa.
Netilmicin sulfate is soluble easily in water, has unsaturated double-bond, injection producing and storing in Netilmicin structure Easy oxidation discoloration in journey.The preparation of kind listing at present has small-volume injection, freeze drying powder injection, high-capacity injection, but raw There is phenomena such as different degrees of oxidation stain, related substance increase during production and storage.According to experimental result and related text Report is offered, the principal element for influencing its injection quality is:The pH value of oxygen, liquid in sterilising temp, air, and it sterilizes Temperature is not easy more than 105 DEG C, otherwise content decline, colour changed into yellow, and related substance is significantly raised.This means that the injection of this product Agent is not easy to produce using terminal sterilization method.So presently, there are dosage forms:The production of small-volume injection, high-capacity injection routine Method (100 DEG C of sterilizings) not can fully ensure that sterility requirements, especially high-capacity injection risk bigger;Freeze drying powder injection, nothing Though bacterium ensures that 10 can be reached-3Level, but there are preparation processes it is complicated, cost is higher, and Clinical practice need to redissolve the shortcomings of.
102451154 A of CN (201010520937.3, Fang Ming) disclose a kind of netilmicin sulfate injection and its system Preparation Method.It is characterized in that:50,000,000 unit of sulfur acid Netilmicin in every 1000 milliliters of injections, 0.5~2g of antioxidant, network 0.1~1g of mixture, pH value is between 5.3~5.7.Its preparation process is:Under the conditions of air purity is hundred grades, it will match in right amount System is cooled to 30 DEG C hereinafter, logical nitrogen deoxygenation, will make in the antioxidant of recipe quantity, complexing agent addition water for injection with water for injection It is completely dissolved, the netilmicin sulfate of recipe quantity is added in above-mentioned solution, stirring makes to be completely dissolved, with 0.05~0.2% (g/ M1) the needle-use activated carbon absorption of concentration, takes off charcoal with 1 μm of filter, 1 set of initial filter, and pH is adjusted 5.3~5.7 with liquor sodii citratis Between, stir evenly, full dose be settled to water for injection, with 1 set of 0.22/0.22 μm of polypropylene foldable filter element filter and 0.22/0.22 2 sets of refined filtration degermings of μm microporous membrane of polyethersulfone candle filter, embedding (the overall process inflated with nitrogen) under the conditions of hundred grades, 100 DEG C or less assisted sterilizations, lamp inspection are packed to obtain the final product.It is believed that the prescription and technique of this invention science ensure that how sulfuric acid replaces rice The stability of star injection, the preparation method of sterile+assisted sterilization improve the sterility assurance level of drug.It is unluckily Be the invention technique effect it is unsatisfactory.
CN102525963B (201210027259.6, general life) discloses a kind of Netilmicin sulfate lyophiled powder injection and its system Netilmicin sulfate and additives are added water to be made into netilmicin sulfate suspension by Preparation Method, freeze-dried that how sulfuric acid replaces Rice star freeze-dried powder, wherein additives are container molecule and pH adjusting agent, and container molecule is selected from bletilla polysaccharide, beta-cyclodextrin, urine Element, thiocarbamide, beta-cyclodextrin derivative, deoxycholic aicd and starch, pH adjusting agent be selected from sodium carbonate, sodium bicarbonate, ammonium hydroxide, sulfuric acid and Phosphoric acid.Auxiliary material needed for the present invention is few, and preparation process is simple, especially carries out screening and optimizing to lyophilized technique, has stability strong, raw The features such as object availability is high, production cost is low, and quality safety is reliable.In addition, CN103610653A (201310615602.3, lead to With) a kind of preparation method of injection netilmicin sulfate freeze-dried powder is disclosed, added by the adjustment to processing step, such as drug Add the adjustment of sequence, and for temperature, duration, pressure and other parameters are precisely controlled, also to multi layer control of filtering etc. so that To the quality of finished product obtain great promotion, improve the pot-life, process more specification, be suitable for promoting.Do not consider for the time being The technique effect of these powder-injection, however the high production technology cost of freeze drying powder injection and this cheap drug and unbecoming.
Therefore it provides a kind of netilmicin sulfate injection with excellent pharmaceutical properties, and to this injection into The method of row quality control is still that those skilled in the art expect very much;Such as expect prepared netilmicin sulfate note Penetrating liquid has excellent chemical stability, and effectively to this method etc. for carrying out quality control, this is for clinical application For be very useful.
Invention content
For this purpose, the purpose of the present invention is to provide a kind of new methods to prepare netilmicin sulfate injection, and phase Wait for that netilmicin sulfate injection prepared by these methods has excellent quality index and/or has excellent stability.This Inventor using the netilmicin sulfate injection that the method for the present invention obtains surprisingly it has been found that have one or more aspects Excellent properties.It finds and is accomplished the present invention is based on this.
For this purpose, first aspect present invention provides the method for preparing netilmicin sulfate injection, the Netilmicin note It penetrates in liquid and includes:Netilmicin sulfate, sodium sulfite or sodium hydrogensulfite, cysteine, natrium adetate or mosatil, And water for injection;This method comprises the following steps:
(1) cysteine and netilmicin sulfate raw material are added into the water for injection of amount of preparation 20%, stirring keeps its molten 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added into the liquid for solution;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, to the medicine 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in liquid;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optionally The pH with acid-base modifier regulating liquid medicine in 5.0~7.0 ranges, benefit adds to the full amount of water for injection;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into clearly Wash sterilizing ampoule bottle in, carry out nitrogen filling after seal, carry out flowing steam sterilization processing after, leak detection to get.
The method of any embodiment according to a first aspect of the present invention, used in water for injection water temperature 40 DEG C with Under.
It is optional in the method for any embodiment according to a first aspect of the present invention, wherein step (3) to use acid-base modifier The pH of regulating liquid medicine is in 5.5~6.5 ranges.
Flowing steam sterilization, which is handled, in the method for any embodiment according to a first aspect of the present invention, wherein step (4) is Flowing steam sterilization is handled 30 minutes at 100 DEG C.
The method of any embodiment according to a first aspect of the present invention, wherein the sulphite is sodium sulfite or sulfurous Sour hydrogen sodium.
The method of any embodiment according to a first aspect of the present invention, wherein the edetate be natrium adetate or according to Ground acid calcium sodium.
The method of any embodiment according to a first aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 1~200,000,
1~10mg of sodium sulfite or sodium hydrogensulfite,
0.1~2mg of cysteine,
Natrium adetate or 0.05~1mg of mosatil and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a first aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 2~100,000,
2~9mg of sodium sulfite or sodium hydrogensulfite,
0.2~1mg of cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a first aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 2~100,000,
2~9mg of sodium sulfite or sodium hydrogensulfite,
0.2~1mg of cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a first aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 2~100,000,
2~9mg of sodium sulfite,
0.2~1mg of cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a first aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 2~100,000,
2~9mg of anhydrous sodium sulfite,
0.2~1mg of cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a first aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 2~100,000,
2~9mg of anhydrous sodium sulfite,
0.2~1mg of L-cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a first aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 2~100,000,
2~9mg of anhydrous sodium sulfite,
0.2~1mg of L-cysteine,
0.1~0.6mg of natrium adetate and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a first aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 3~80,000,
2~5mg of anhydrous sodium sulfite,
0.2~0.6mg of L-cysteine,
0.1~0.5mg of natrium adetate and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a first aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
50,000 U of netilmicin sulfate,
Anhydrous sodium sulfite 3mg,
L-cysteine 0.4mg,
Natrium adetate 0.2mg and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a first aspect of the present invention, wherein its pH of the netilmicin sulfate injection exists In 5.0~7.0 ranges, preferably its pH is in 5.5~6.5 ranges.
The method of any embodiment according to a first aspect of the present invention, wherein the acid-base modifier is hydrochloric acid or hydrogen-oxygen Change sodium, such as 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.In one embodiment, the dosage of the acid-base modifier is to make The pH of the injection is obtained in 5.0~7.0 ranges, preferably its pH is in 5.5~6.5 ranges.
Further, second aspect of the present invention provides a kind of netilmicin sulfate injection, wherein including:How sulfuric acid replaces Meter Xing, sodium sulfite or sodium hydrogensulfite, cysteine, natrium adetate or mosatil and water for injection.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention includes per in 1ml:
The U of netilmicin sulfate 1~200,000,
1~10mg of sodium sulfite or sodium hydrogensulfite,
0.1~2mg of cysteine,
Natrium adetate or 0.05~1mg of mosatil and
Water for injection adds to 1ml in right amount.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention includes per in 1ml:
The U of netilmicin sulfate 2~100,000,
2~9mg of sodium sulfite or sodium hydrogensulfite,
0.2~1mg of cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention includes per in 1ml:
The U of netilmicin sulfate 2~100,000,
2~9mg of sodium sulfite or sodium hydrogensulfite,
0.2~1mg of cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention includes per in 1ml:
The U of netilmicin sulfate 2~100,000,
2~9mg of sodium sulfite,
0.2~1mg of cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention includes per in 1ml:
The U of netilmicin sulfate 2~100,000,
2~9mg of anhydrous sodium sulfite,
0.2~1mg of cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention includes per in 1ml:
The U of netilmicin sulfate 2~100,000,
2~9mg of anhydrous sodium sulfite,
0.2~1mg of L-cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention includes per in 1ml:
The U of netilmicin sulfate 2~100,000,
2~9mg of anhydrous sodium sulfite,
0.2~1mg of L-cysteine,
0.1~0.6mg of natrium adetate and
Water for injection adds to 1ml in right amount.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention includes per in 1ml:
The U of netilmicin sulfate 3~80,000,
2~5mg of anhydrous sodium sulfite,
0.2~0.6mg of L-cysteine,
0.1~0.5mg of natrium adetate and
Water for injection adds to 1ml in right amount.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention includes per in 1ml:
50,000 U of netilmicin sulfate,
Anhydrous sodium sulfite 3mg,
L-cysteine 0.4mg,
Natrium adetate 0.2mg and
Water for injection adds to 1ml in right amount.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention, pH is in 5.0~7.0 ranges Interior, preferably its pH is in 5.5~6.5 ranges.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention, in order to adjust the need of pH value It wants, wherein can also include acid-base modifier.In one embodiment, the acid-base modifier is hydrochloric acid or hydroxide Sodium, such as 1M hydrochloric acid solutions or 1M sodium hydroxide solutions.In one embodiment, the dosage of the acid-base modifier be so that The pH of the injection is in 5.0~7.0 ranges, and preferably its pH is in 5.5~6.5 ranges.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention is to shine to include the following steps Method be prepared:
(1) cysteine and netilmicin sulfate raw material are added into the water for injection of amount of preparation 20%, stirring keeps its molten 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added into the liquid for solution;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, to the medicine 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in liquid;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optionally The pH with acid-base modifier regulating liquid medicine in 5.0~7.0 ranges, benefit adds to the full amount of water for injection;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into clearly Wash sterilizing ampoule bottle in, carry out nitrogen filling after seal, carry out flowing steam sterilization processing after, leak detection to get.
The netilmicin sulfate injection of any embodiment according to a second aspect of the present invention, used in water for injection Water temperature at 40 DEG C or less.
In the netilmicin sulfate injection of any embodiment according to a second aspect of the present invention, wherein step (3) optionally The pH with acid-base modifier regulating liquid medicine in 5.5~6.5 ranges.
Circulation in the netilmicin sulfate injection of any embodiment according to a second aspect of the present invention, wherein step (4) Steam sterilizing processing is that flowing steam sterilization is handled 30 minutes at 100 DEG C.
Further, third aspect present invention provides detection method of the netilmicin sulfate injection in relation to substance, institute It states in netilmicin sulfate injection and includes:Netilmicin sulfate, sulphite, cysteine, edetate and injection Water, this approach includes the following steps:
Precision measurement netilmicin sulfate injection is appropriate, is quantitatively diluted and is made in every 1ml containing about Netilmicin with water The solution of 2.0mg, as test solution;It is appropriate to measure test solution, is quantitatively diluted and is made in every 1ml containing about how replacing with water The solution of each 25 μ g of rice star, 50 μ g, 100 μ g, as a contrast solution (1), (2), (3).According to high performance liquid chromatography (version in 2015 Four general rules 0512 of Chinese Pharmacopoeia) it measures, it is filler (pH value range 0.8~8.0) with octadecyl silane;With 0.2mol/L trifluoroacetic acid solutions (also including 0.02mol/L tartaric acid in the solution)-methanol (84:16) it is mobile phase, flow velocity For 0.5ml per minute;(reference conditions are detected with evaporative light scattering detector:100 DEG C of drift tube temperature, flow rate of carrier gas are every point Clock 2.6L).Take Netilmicin standard items and Etimicin reference substance each appropriate, being dissolved in water and diluting is made in every 1ml respectively about Mixed solution containing 0.2mg takes 20 μ l injection liquid chromatographs, records chromatogram, point at Netilmicin peak and Etimicin peak 1.2 are should be greater than from degree.Contrast solution (1), (2), (3) each 20 μ l are taken immediately, is injected separately into liquid chromatograph, record chromatogram, Equation of linear regression, related coefficient (r) Ying Bu little are calculated with the logarithm of contrast solution concentration and the logarithm of corresponding peak area In 0.99;It is another to take 20 μ l injection liquid chromatographs of test solution, 2 times of record chromatogram to principal component peak retention time.Knot Fruit calculates:For Netilmicin injection, States Pharmacopoeia specifications require in test solution chromatogram if any impurity peaks (sulfuric acid peak And except other auxiliary material peaks), it is calculated with equation of linear regression, single impurity must not cross the 3.0% of labelled amount, and total impurities must not Cross the 6.0% of labelled amount.
The method of any embodiment according to a third aspect of the present invention, wherein the sulphite is sodium sulfite or sulfurous Sour hydrogen sodium.
The method of any embodiment according to a third aspect of the present invention, wherein the edetate be natrium adetate or according to Ground acid calcium sodium.
The method of any embodiment according to a third aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 1~200,000,
1~10mg of sodium sulfite or sodium hydrogensulfite,
0.1~2mg of cysteine,
Natrium adetate or 0.05~1mg of mosatil and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a third aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 2~100,000,
2~9mg of sodium sulfite or sodium hydrogensulfite,
0.2~1mg of cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a third aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 2~100,000,
2~9mg of sodium sulfite or sodium hydrogensulfite,
0.2~1mg of cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a third aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 2~100,000,
2~9mg of sodium sulfite,
0.2~1mg of cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a third aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 2~100,000,
2~9mg of anhydrous sodium sulfite,
0.2~1mg of cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a third aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 2~100,000,
2~9mg of anhydrous sodium sulfite,
0.2~1mg of L-cysteine,
Natrium adetate or 0.1~0.6mg of mosatil and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a third aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 2~100,000,
2~9mg of anhydrous sodium sulfite,
0.2~1mg of L-cysteine,
0.1~0.6mg of natrium adetate and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a third aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
The U of netilmicin sulfate 3~80,000,
2~5mg of anhydrous sodium sulfite,
0.2~0.6mg of L-cysteine,
0.1~0.5mg of natrium adetate and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a third aspect of the present invention, wherein the netilmicin sulfate injection is per 1ml In include:
50,000 U of netilmicin sulfate,
Anhydrous sodium sulfite 3mg,
L-cysteine 0.4mg,
Natrium adetate 0.2mg and
Water for injection adds to 1ml in right amount.
The method of any embodiment according to a third aspect of the present invention, wherein its pH of the netilmicin sulfate injection exists In 5.0~7.0 ranges, preferably its pH is in 5.5~6.5 ranges.
The method of any embodiment according to a third aspect of the present invention, wherein may be used also in the netilmicin sulfate injection To include acid-base modifier.In one embodiment, the acid-base modifier is hydrochloric acid or sodium hydroxide, such as 1M salt Acid solution or 1M sodium hydroxide solutions.In one embodiment, the dosage of the acid-base modifier is so that the injection PH in 5.0~7.0 ranges, preferably its pH is in 5.5~6.5 ranges.
In the above method of the present invention the step of, although the specific steps of its description are in certain details or language description Step different from described in the upper and example of following detailed description part, however, those skilled in the art according to The detailed disclosure of full text of the present invention can summarize approach described above step completely.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted for other realities The technical characteristic in scheme is applied, as long as they are not in contradiction.The invention will be further described below.
All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literary When offering expressed meaning and the inconsistent present invention, it is subject to the statement of the present invention.In addition, the various terms that use of the present invention and Phrase has that well known to a person skilled in the art general senses, nonetheless, the present invention remain desirable at this to these terms and Phrase is described in more detail and explains, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention Subject to the meaning stated.
In the present invention, if not otherwise indicated, using to reagent and raw material be to buy from the market.
Refer to international unit when referring to the measurement unit U or ten thousand U of active constituent netilmicin sulfate in this present invention IU or ten thousand IU.
Netilmicin belongs to aminoglycoside antibiotics, and antibacterial action is substantially similar to gentamicin, to enterobacteriaceae lactobacteriaceae Such as Escherichia coli, Klebsiella, Enterobacter, Proteus, Shigella, Salmonella, bacillus citrate category, Sha Lei The good antibacterial action of the tools such as Pseudomonas, Pseudomonas aeruginosa, nitrate-negative bacillus.
Meningococcus and Bacillus influenzae are also most sensitive to it.Effect of this product to Pu Luofeideng Pseudomonas, Serratia Not as good as gentamicin, tobramycin is not so good as to the effect of Pseudomonas aeruginosa, but to staphylococcus and other gram-positive coccis Effect is then better than other aminoglycosides;This product has antibacterial action to part methicillin resistance bacterium, to pneumococcus, each group chain The effect of coccus is poor, to enterococcus spp and anaerobic bacteria without effect.This product stablizes certain aminoglycosides inactive enzymes, therefore right Part gentamicin drug-fast bacteria is still valid.
How Netilmicin, English name Netilmicin, the vertical bacterium jinx of Chinese nickname, at once bacterium star netilmicin, replace Mycin, netilmicin, ethyl sisomicin, English alias Certomycin, Gertomycin, Netillin, Netilyn, Netrocin, Netromicime, Nettacin, Western medicine drug.
The characteristics of antimicrobial spectrum of Netilmicin is approximate with the big element of celebrating, this product is steady to Aminoglycoside transacetylase AAC (3) It is fixed.To the drug resistant bacterial strain such as generating the enzyme and making kanamycins, gentamicin, tobramycin, sisomicin, this product can be sensitive. It is absorbed rapidly after intramuscular injection, blood peak concentration of drug occurs in 30-60 points.By 2mg/kg injections, blood peak concentration of drug is up to 7 μ g/ml.It presses Prescribed dose is administered, and blood concentration is less than 3 μ g/ml after 8 hours.The half-life period of this product is 2-2.5 hours, is not become with route of administration Change, but then half-life period can extend and (is administered by 3mg/kg, t1/2 is 3 hours) when dosage increasing.80% drug is in 24 hours It is drained from urine, drug usine level can be more than 100 μ g/ml.
Netilmicin is not metabolized in vivo.Every 12 hours administration 1-4mg/kg, can reach stable state the 2nd time in medication.This product It is distributed widely in each main organs and each body fluid, but concentration is low in cerebrospinal fluid and bile.Due to this product can enter ascites or In edematous fluid, therefore, the blood concentration of such patient is often less than other patients.The blood concentration of fever patient, which is also often less than, does not generate heat Person, but blood concentration can be increased slightly after bringing down a fever.This product antibacterial action is substantially similar to gentamicin, for example big to enterobacteriaceae lactobacteriaceae Enterobacteria, Klebsiella, Enterobacter, Proteus, Shigella, Salmonella, bacillus citrate category, husky thunder bacterium The good antibacterial action of the tools such as category, Pseudomonas aeruginosa, nitrate-negative bacillus.
Meningococcus and Bacillus influenzae are also most sensitive to it.Effect of this product to Pu Luofeideng Pseudomonas, Serratia Not as good as gentamicin, tobramycin is not so good as to the effect of Pseudomonas aeruginosa, but to staphylococcus and other gram-positive coccis Effect is then better than other aminoglycosides;This product has antibacterial action to part methicillin resistance bacterium, to pneumococcus, each group chain The effect of coccus is poor, to enterococcus spp and anaerobic bacteria without effect.This product stablizes certain aminoglycosides inactive enzymes, therefore right Part gentamicin drug-fast bacteria is still valid.
Netilmicin pharmacological characteristics are similar to gentamicin.Rapid and complete, 1 intramuscular injection 1mg/ of adult is absorbed after intramuscular injection After kg, blood peak concentration of drug 0.5~1h arrival after administration of 3.76mg/L;Average blood medicine peak after intramuscular injection 2mg/kg and 3mg/kg Concentration is respectively up to 11.8mg/L and 15.8mg/L;1 intravenous infusion (drips off) the blood peak concentration of drug after 2mg/kg in 30min 0.9mg/L can be still measured after 16.8mg/L, 8h.This product is mainly discharged through glomerular filtration, in urinating for 24 hours discharge rate be about 60%~ 90%;Serum half life is 2~2.5h.This product is distributed widely in each main stolen goods device and body fluid, in cortex renis, kidney medulla and breast Head has accumulation, but concentration is low in cerebrospinal fluid and bile.
The clinical indication of netilmicin sulfate injection is mainly:Suitable for caused by sensitive bacterial include new life The short of serious or threat to life bacterial infection disease including each age patient such as youngster, baby, children.These senses Infectious diseases include:
(1) complexity urinary tract infections:By Escherichia coli, klebsiella pneumoniae, Pseudomonas aeruginosa, enterobacteria Belong to bacterium, proteus mirabilis, Proteus bacterium (indole-positive), Serratia and citric acid bacterium genus bacterium and golden yellow Staphylococcus etc. causes;
(2) septicemia:By Escherichia coli, klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter and Sha Lei Campylobacter bacteria and proteus mirabilis etc. cause;
(3) skin soft-tissue infection:By Escherichia coli, klebsiella pneumoniae, Pseudomonas aeruginosa, enterobacteria Belong to and Serratia bacterium, proteus mirabilis, Proteus bacterium (indole-positive) and staphylococcus aureus (penicillin Enzyme and non-penicillase zymogenic bacteria) etc. cause;
(4) intraperitoneal infection, including peritonitis and intraabdominal abscesses:By Escherichia coli, klebsiella pneumoniae, green Purulence pseudomonad, Enterobacter bacterium, proteus mirabilis, Proteus bacterium (indole-positive) and staphylococcus aureus (penicillase and non-penicillase zymogenic bacteria) etc. causes;
(5) lower respiratory tract infection:By Escherichia coli, klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter With Serratia bacterium, proteus mirabilis, Proteus bacterium (indole-positive) and staphylococcus aureus (penicillase With non-penicillase zymogenic bacteria) etc. cause.
The clinical usage and dosage of netilmicin sulfate injection is as follows:In order to be computed correctly dosage, should know before administration The weight of patient should be calculated the dosage of adiposis patient by the weight of lath.Renal function state can be according to serum creatinine concentration Measurement and estimate, or calculated according to inherent creatinine clearance rate.In addition, renal function should be inspected periodically during treatment.For The patient that body surface is excessively burnt, since medicine moves the change of parameter, serum drug level may decline, by measuring serum drug Concentration, which carrys out direction of medication usage dosage, seems more important.The course for the treatment of:Under the premise of ensureing curative effect, treatment time should be shortened as far as possible.It is logical The normal course for the treatment of is 7-14 days, when there is accompanying infection, it may be necessary to longer treatment time.Although the extended treatment time, how rice is replaced The tolerance of star is good, but is administered for a long time, should detect renal function, hearing and vestibular function, if clinic has characterization, should adapt to adjust Whole dosage.In application process, should by measure serum drug level peak-to-valley value, with ensure to dosage under it is effective and Safety.When assay method is feasible, Cmax ranging from 4-12mcg/ml, no more than 16mcg/ml.Between individual, due to kidney function The difference of energy state (normal or abnormal), drug concentration can become, and Cmax should be controlled in 6-12mcg/ml, and Grain volume should control It is preferable in 0.5-2mcg/ml.For the validity of the serum drug level of especial patient, it is considered as sensibility, the sense of pathogenic bacteria The function of the severity of dye and the immunity of organism defence system of patient.Recommended dose is not unalterable, is only used as and controls for the first time One guidance of selection dosage when treating or blood concentration cannot be measured during treating.For the newborn (baby within being born 6 weeks Youngster):Daily medication total amount is 4.0-6.5mg/kg, and every 12 hours primary, and each dosage is 2.0-3.25mg/kg.For baby (birth 6 weeks or more) was to 12 years old children:Daily medication total amount is 5.5-8.0mg/kg, can be primary for every eight hours, each dosage 1.8-2.7mg/kg;Can also every 12 hours it is primary, each dosage is 2.7-4.0mg/kg.The dosage of renal impairment patient: For renal impairment patient, the necessary individuation of dosage, to ensure effective treatment concentration.Adjustment dosage method have it is several, But most accurate method is adjusted based on blood concentration.If blood concentration cannot obtain, and the renal function of patient is steady Fixed, it is most reliable to survey its serum creatinine level and creatinine clearance rate.If renal function further deteriorates, dosage needs to subtract significantly It is few.For normal renal function patient, predose is identical with recommended dose.There is the trouble damaged in various degree for renal function Person, whole day dosage can adjust dosage by the following method.For normal renal function patient, according to serum creatinine concentration, The individual dose of patient is adjusted by the dosage recommended.
If creatinine clearance rate through serum creatinine level it is known that or can calculate and obtain, adjustable dosage.
The creatinine clearance rate of normal person can be computed by serum creatinine level and be obtained.The normal creatinine of adult female is removed Normal creatinine clearance rate × 85% of rate=adult human male.(i.e. every 24 hours use can be administered in every daily amount of adjustment once a day Medicine 1 time), it can also be administered for daily 2-3 time (i.e. every medication in 8 or 12 hours 1 time).In general, single dose is no more than 3.25mg/kg.For receiving the potential renal insufficiency patient of hemodialysis, through dialyse removed dose with it is used Instrument and equipment is related with method.Phase between dialysis recommends adult to supplement Netilmicin by 2.0mg/kg, until blood concentration reaches institute Need concentration.In addition, dosage is still adjusted according to monitoring result.
The positive effect of the present invention is that:The method of the present invention can be effectively used for preparing with excellent properties Netilmicin sulfate injection has good market application prospect.
Specific implementation mode
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited In following embodiments.One of skill in the art, can be with it is understood that under the premise of without departing substantially from the spirit and scope of the present invention Various change and modification are carried out to the present invention.The present invention carries out the material and test method that are arrived used in experiment general And/or specific description.Although to realize the present invention many materials and operating method used in purpose be it is known in the art that But the present invention is still described in detail as far as possible herein.Following embodiment further illustrates the present invention, rather than limits this hair It is bright.
Hereafter preparation process in order to citing purpose, and the comparability based on each citing and make some specific description, Those skilled in the art can therefrom summarize to obtain the present invention program according to existing knowledge completely.Below how rice is being replaced with Sulphuric acid Use is the same as a batch of netilmicin sulfate bulk pharmaceutical chemicals when star injection.When preparing netilmicin sulfate injection below, with Amount per 1ml lists prescription, but when actually feeding intake, each batches amount is the amount of 5000ml.
Test example 1:The experiment of Related substances separation and assay and method in injection
Precision measurement netilmicin sulfate injection is appropriate, is quantitatively diluted and is made in every 1ml containing about Netilmicin with water The solution of 2.0mg, as test solution;It is appropriate to measure test solution, is quantitatively diluted and is made in every 1ml containing about how replacing with water The solution of each 25 μ g of rice star, 50 μ g, 100 μ g, as a contrast solution (1), (2), (3).According to high performance liquid chromatography (version in 2015 Four general rules 0512 of Chinese Pharmacopoeia) it measures, it is filler (pH value range 0.8~8.0) with octadecyl silane;With 0.2mol/L trifluoroacetic acid solutions (also including 0.02mol/L tartaric acid in the solution)-methanol (84:16) it is mobile phase, flow velocity For 0.5ml per minute;(reference conditions are detected with evaporative light scattering detector:100 DEG C of drift tube temperature, flow rate of carrier gas are every point Clock 2.6L).Take Netilmicin standard items and Etimicin reference substance each appropriate, being dissolved in water and diluting is made in every 1ml respectively about Mixed solution containing 0.2mg takes 20 μ l injection liquid chromatographs, records chromatogram, point at Netilmicin peak and Etimicin peak 1.2 are should be greater than from degree.Contrast solution (1), (2), (3) each 20 μ l are taken immediately, is injected separately into liquid chromatograph, record chromatogram, Equation of linear regression, related coefficient (r) Ying Bu little are calculated with the logarithm of contrast solution concentration and the logarithm of corresponding peak area In 0.99;It is another to take 20 μ l injection liquid chromatographs of test solution, 2 times of record chromatogram to principal component peak retention time.Knot Fruit calculates:For Netilmicin injection, States Pharmacopoeia specifications require in test solution chromatogram if any impurity peaks (sulfuric acid peak And except other auxiliary material peaks), it is calculated with equation of linear regression, single impurity must not cross the 3.0% of labelled amount, and total impurities must not Cross the 6.0% of labelled amount.
The netilmicin sulfate injection of Examples below 1~10 is measured using above-mentioned Related substances separation method, as a result Show that the single impurity of each injection and total impurities disclosure satisfy that the above-mentioned regulation of pharmacopeia.Use above-mentioned Related substances separation Method measures the netilmicin sulfate injection of Examples below 1~10, as a result shows between Netilmicin and cysteine Separating degree is in 3.2~3.4 ranges, and when not adding tartaric acid in mobile phase, between Netilmicin and cysteine Separating degree in 1.5~1.7 ranges, although this field usually require that separating degree be more than 1.5 and above range can still meet It is general to require, however it is well known that the higher result of calculation of separating degree is more accurate, this field has been generally acknowledged that separating degree is more than 2.0 When be can be satisfactory.This result shows that, the injection of cysteine is added to for the present invention, to improve analysis side The effect of method, appropriate change flowing phase composition is beneficial.
In addition, also preparing a kind of sisomicin (being believed to be impurity that can be generated by Netilmicin hydrolysis) solution with water (50 μ g/ml), solution (4) as a contrast, for the sisomicin impurity in injection (or bulk pharmaceutical chemicals) carry out it is qualitative and Quantitative determination.
In addition, it is (dense also to use Netilmicin standard items (deriving from National Institute for Food and Drugs Control) to prepare contrast solution Degree is about 200mg/ml, and injection is also diluted to suitable concentration), measure in injection how to replace rice according to the above-mentioned method in relation to substance Star content.
Injection study on the stability:The injection that each embodiment of text is prepared is removed, 40 DEG C is placed in and places 4 months, survey It is scheduled on the increase percentage of sisomicin impurity before and after this high-temperature treatment, i.e.,:[(- 0 month impurity content of impurity content in April) ÷ 0 month Impurity content] × 100%.The results show that the increase by hundred for the 10 batches of injection sisomicin impurity that embodiment 1-10 is prepared Score is in 23~38% ranges.The increase percentage 127% for the injection sisomicin impurity that embodiment 11 is prepared. In addition, with reference to the formula and preparation method of embodiment 1-10, different is only that the L-cysteine in each prescription is changed to half Guang ammonia of D- Acid, 10 batches of obtained injections investigate method processing according to aforementioned stable, and as a result the increase percentage of sisomicin impurity exists In 88~165% ranges.In addition, with reference to the formula and preparation method of embodiment 1-10, different is only throughout in side without using half Cystine, 10 batches of obtained injections investigate method processing according to aforementioned stable, as a result the increase percentage of sisomicin impurity In 103~188% ranges.
Assay:Determination of Netilmicin (C1 is indicated with mg/ml) in injection is measured using above-mentioned HPLC methods, in addition With active medicine inventory and the final theoretical content (C0, with mg/ml tables for calculating Netilmicin in injection with liquid product Show), the relative amount (%) of active constituent is calculated with (C1 ÷ C2) × 100%.As a result, the relative amount of Examples below 1-10 (%) is in 99~101% ranges.In addition, with reference to the formula and preparation method of embodiment 1-10, different be only make step (1) and (2) merge, netilmicin sulfate, cysteine, sulphite and edetate are handled with activated carbon after dissolving together, obtained 10 batches of injections carry out assay through the above method and calculate relative amount, and as a result the relative amount of 10 batches of injections is 92 In~95% range, show this to have apparent active ingredient loss with liquid method.
Embodiment 1:Prepare netilmicin sulfate injection
Formula:
50,000 U of netilmicin sulfate,
Anhydrous sodium sulfite 3mg,
L-cysteine 0.4mg,
Natrium adetate 0.2mg and
Water for injection adds to 1ml in right amount.
Preparation method:
(1) to cysteine and sulfuric acid being added in the water for injection of amount of preparation 20% (water temperature is at 40 DEG C hereinafter, similarly hereinafter) how It for rice star raw material, stirs to dissolve, 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering is added into the liquid;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, to the medicine 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in liquid;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optionally The pH with acid-base modifier regulating liquid medicine in 5.5~6.5 ranges, benefit adds to the full amount of water for injection;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into clearly It washes in sterilizing ampoule bottle, is sealed after carrying out nitrogen filling, carry out flowing steam sterilization processing (at 100 DEG C flowing steam sterilization Processing 30 minutes) after, leak detection to get.
Embodiment 2:Prepare netilmicin sulfate injection
Formula:
20,000 U of netilmicin sulfate,
Anhydrous sodium sulfite 9mg,
L-cysteine 0.2mg,
Natrium adetate 0.6mg and
Water for injection adds to 1ml in right amount.
Preparation method:
(1) to cysteine and sulfuric acid being added in the water for injection of amount of preparation 20% (water temperature is at 40 DEG C hereinafter, similarly hereinafter) how It for rice star raw material, stirs to dissolve, 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering is added into the liquid;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, to the medicine 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in liquid;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optionally The pH with acid-base modifier regulating liquid medicine in 6.0~6.5 ranges, benefit adds to the full amount of water for injection;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into clearly It washes in sterilizing ampoule bottle, is sealed after carrying out nitrogen filling, carry out flowing steam sterilization processing (at 100 DEG C flowing steam sterilization Processing 30 minutes) after, leak detection to get.
Embodiment 3:Prepare netilmicin sulfate injection
Formula:
100,000 U of netilmicin sulfate,
Anhydrous sodium sulfite 2mg,
L-cysteine 1mg,
Natrium adetate 0.1mg and
Water for injection adds to 1ml in right amount.
Preparation method:
(1) to cysteine and sulfuric acid being added in the water for injection of amount of preparation 20% (water temperature is at 40 DEG C hereinafter, similarly hereinafter) how It for rice star raw material, stirs to dissolve, 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering is added into the liquid;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, to the medicine 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in liquid;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optionally The pH with acid-base modifier regulating liquid medicine in 5.5~6.0 ranges, benefit adds to the full amount of water for injection;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into clearly It washes in sterilizing ampoule bottle, is sealed after carrying out nitrogen filling, carry out flowing steam sterilization processing (at 100 DEG C flowing steam sterilization Processing 30 minutes) after, leak detection to get.
Embodiment 4:Prepare netilmicin sulfate injection
Formula:
30,000 U of netilmicin sulfate,
Anhydrous sodium sulfite 2mg,
L-cysteine 0.6mg,
Natrium adetate 0.1mg and
Water for injection adds to 1ml in right amount.
Preparation method:
(1) to cysteine and sulfuric acid being added in the water for injection of amount of preparation 20% (water temperature is at 40 DEG C hereinafter, similarly hereinafter) how It for rice star raw material, stirs to dissolve, 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering is added into the liquid;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, to the medicine 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in liquid;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optionally The pH with acid-base modifier regulating liquid medicine in 5.7~6.3 ranges, benefit adds to the full amount of water for injection;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into clearly It washes in sterilizing ampoule bottle, is sealed after carrying out nitrogen filling, carry out flowing steam sterilization processing (at 100 DEG C flowing steam sterilization Processing 30 minutes) after, leak detection to get.
Embodiment 5:Prepare netilmicin sulfate injection
Formula:
80,000 U of netilmicin sulfate,
Anhydrous sodium sulfite 5mg,
L-cysteine 0.2mg,
Natrium adetate 0.5mg and
Water for injection adds to 1ml in right amount.
Preparation method:
(1) to cysteine and sulfuric acid being added in the water for injection of amount of preparation 20% (water temperature is at 40 DEG C hereinafter, similarly hereinafter) how It for rice star raw material, stirs to dissolve, 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering is added into the liquid;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, to the medicine 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in liquid;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optionally The pH with acid-base modifier regulating liquid medicine in 5.5~6.0 ranges, benefit adds to the full amount of water for injection;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into clearly It washes in sterilizing ampoule bottle, is sealed after carrying out nitrogen filling, carry out flowing steam sterilization processing (at 100 DEG C flowing steam sterilization Processing 30 minutes) after, leak detection to get.
Embodiment 6:Prepare netilmicin sulfate injection
Formula:
50,000 U of netilmicin sulfate,
Anhydrous sodium sulfite 4mg,
L-cysteine 0.3mg,
Natrium adetate 0.25mg and
Water for injection adds to 1ml in right amount.
Preparation method:
(1) to cysteine and sulfuric acid being added in the water for injection of amount of preparation 20% (water temperature is at 40 DEG C hereinafter, similarly hereinafter) how It for rice star raw material, stirs to dissolve, 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering is added into the liquid;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, to the medicine 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in liquid;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optionally The pH with acid-base modifier regulating liquid medicine in 6.0~6.5 ranges, benefit adds to the full amount of water for injection;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into clearly It washes in sterilizing ampoule bottle, is sealed after carrying out nitrogen filling, carry out flowing steam sterilization processing (at 100 DEG C flowing steam sterilization Processing 30 minutes) after, leak detection to get.
Embodiment 7:Prepare netilmicin sulfate injection
Formula:
50,000 U of netilmicin sulfate,
Anhydrous sodium sulfite 3mg,
L-cysteine 0.3mg,
Natrium adetate 0.3mg and
Water for injection adds to 1ml in right amount.
Preparation method:
(1) to cysteine and sulfuric acid being added in the water for injection of amount of preparation 20% (water temperature is at 40 DEG C hereinafter, similarly hereinafter) how It for rice star raw material, stirs to dissolve, 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering is added into the liquid;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, to the medicine 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in liquid;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optionally The pH with acid-base modifier regulating liquid medicine in 5.5~6.5 ranges, benefit adds to the full amount of water for injection;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into clearly It washes in sterilizing ampoule bottle, is sealed after carrying out nitrogen filling, carry out flowing steam sterilization processing (at 100 DEG C flowing steam sterilization Processing 30 minutes) after, leak detection to get.
Embodiment 8:Prepare netilmicin sulfate injection
Formula:
7.5 ten thousand U of netilmicin sulfate,
Anhydrous sodium sulfite 5mg,
L-cysteine 0.5mg,
Natrium adetate 0.25mg and
Water for injection adds to 1ml in right amount.
Preparation method:
(1) to cysteine and sulfuric acid being added in the water for injection of amount of preparation 20% (water temperature is at 40 DEG C hereinafter, similarly hereinafter) how It for rice star raw material, stirs to dissolve, 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering is added into the liquid;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, to the medicine 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in liquid;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optionally The pH with acid-base modifier regulating liquid medicine in 5.8~6.3 ranges, benefit adds to the full amount of water for injection;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into clearly It washes in sterilizing ampoule bottle, is sealed after carrying out nitrogen filling, carry out flowing steam sterilization processing (at 100 DEG C flowing steam sterilization Processing 30 minutes) after, leak detection to get.
Embodiment 9:Prepare netilmicin sulfate injection
Formula:
50,000 U of netilmicin sulfate,
Anhydrous sodium sulfite 2.5mg,
L-cysteine 0.25mg,
Natrium adetate 0.25mg and
Water for injection adds to 1ml in right amount.
Preparation method:
(1) to cysteine and sulfuric acid being added in the water for injection of amount of preparation 20% (water temperature is at 40 DEG C hereinafter, similarly hereinafter) how It for rice star raw material, stirs to dissolve, 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering is added into the liquid;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, to the medicine 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in liquid;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optionally The pH with acid-base modifier regulating liquid medicine in 5.5~6.0 ranges, benefit adds to the full amount of water for injection;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into clearly It washes in sterilizing ampoule bottle, is sealed after carrying out nitrogen filling, carry out flowing steam sterilization processing (at 100 DEG C flowing steam sterilization Processing 30 minutes) after, leak detection to get.
Embodiment 10:Prepare netilmicin sulfate injection
Formula:
2.5 ten thousand U of netilmicin sulfate,
Anhydrous sodium sulfite 2mg,
L-cysteine 0.2mg,
Natrium adetate 0.25mg and
Water for injection adds to 1ml in right amount.
Preparation method:
(1) to cysteine and sulfuric acid being added in the water for injection of amount of preparation 20% (water temperature is at 40 DEG C hereinafter, similarly hereinafter) how It for rice star raw material, stirs to dissolve, 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering is added into the liquid;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, to the medicine 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in liquid;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optionally The pH with acid-base modifier regulating liquid medicine in 6.0~6.5 ranges, benefit adds to the full amount of water for injection;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into clearly It washes in sterilizing ampoule bottle, is sealed after carrying out nitrogen filling, carry out flowing steam sterilization processing (at 100 DEG C flowing steam sterilization Processing 30 minutes) after, leak detection to get.
Embodiment 11:Prepare netilmicin sulfate injection
Under the conditions of air purity is hundred grades, 700ml waters for injection are taken, are cooled to 30 DEG C or so, led to N210 minutes, add Enter sodium hydrogensulfite 1g, natrium adetate 0.1g stirrings make to be completely dissolved, the netilmicin sulfate stirring of 50,000,000 units of addition Make to be completely dissolved, be adsorbed 15 minutes with the needle-use activated carbon of 0.1% (g/ml) concentration, takes off charcoal with 1 μm of filter, 1 set of initial filter, mend Nearly 1000ml is injected water to, pH is adjusted between 5.3~5.7 with 10% liquor sodii citratis, stirs evenly, add injection With water to 1000ml, filtered with 1 set and 0.22/0.22 μm microporous membrane of polyethersulfone of 0.22/0.22 μm of polypropylene foldable filter element filter The 2 sets of refined filtration degermings of core filter, embedding (the overall process inflated with nitrogen) under the conditions of hundred grades, 100 DEG C, 30 minutes assisted sterilizations, lamp inspection, It packs to obtain the final product.(154#)
Industrial applicability
The invention belongs to medicine manufacture technology fields, are related to a kind of netilmicin sulfate product and its preparation method, especially It is related to a kind of netilmicin sulfate injection and its preparation method.Netilmicin sulfate injection according to the present invention, The excellent effect of other aspects is also optionally presented.

Claims (15)

1. the method for preparing netilmicin sulfate injection, group of the Netilmicin injection per 1ml becomes:How sulfuric acid replaces rice The U of star 2 ~ 100,000,2 ~ 9mg of anhydrous sodium sulfite, 0.2 ~ 1mg of L-cysteine, natrium adetate or mosatil 0.1 ~ 0.6mg and water for injection add to 1ml and optional acid-base modifier in right amount;This method comprises the following steps:
(1) cysteine and netilmicin sulfate raw material are added into the water for injection of amount of preparation 20%, stirs to dissolve, to 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in the liquid;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, into the liquid 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering is added;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optional uses acid In 5.0 ~ 7.0 ranges, benefit adds to the full amount of water for injection the pH of alkali conditioning agent regulating liquid medicine;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into cleaning and is gone out In bacterium ampoule bottle, carry out nitrogen filling after seal, carry out flowing steam sterilization processing after, leak detection to get.
2. the method according to claim 1, used in water for injection water temperature at 40 DEG C or less.
3. the method according to claim 1, the optional pH with acid-base modifier regulating liquid medicine is in 5.5 ~ 6.5 models in step (3) In enclosing.
4. the method according to claim 1, flowing steam sterilization processing is at 100 DEG C at flowing steam sterilization in step (4) Reason 30 minutes.
5. the method according to claim 1, the netilmicin sulfate injection becomes per 1ml groups:Netilmicin sulfate 2 ~ 10 Ten thousand U, 2 ~ 9mg of anhydrous sodium sulfite, 0.2 ~ 1mg of L-cysteine, 0.1 ~ 0.6mg of natrium adetate and water for injection add in right amount To 1ml.
6. the method according to claim 1, the netilmicin sulfate injection becomes per 1ml groups:Netilmicin sulfate 3 ~ 80,000 U, 2 ~ 5mg of anhydrous sodium sulfite, 0.2 ~ 0.6mg of L-cysteine, 0.1 ~ 0.5mg of natrium adetate and water for injection add in right amount To 1ml.
7. the method according to claim 1, the netilmicin sulfate injection becomes per 1ml groups:50,000 U of netilmicin sulfate, Anhydrous sodium sulfite 3mg, L-cysteine 0.4mg, natrium adetate 0.2mg and water for injection add to 1ml in right amount.
8. a kind of netilmicin sulfate injection becomes per 1ml groups:The U of netilmicin sulfate 2 ~ 100,000, anhydrous sodium sulfite 2 ~ 9mg, 0.1 ~ 0.6mg of 0.2 ~ 1mg of L-cysteine, natrium adetate or mosatil, water for injection add to 1ml in right amount, with And optional acid-base modifier;The netilmicin sulfate injection is prepared according to the method included the following steps:
(1) cysteine and netilmicin sulfate raw material are added into the water for injection of amount of preparation 20%, stirs to dissolve, to 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering are added in the liquid;
(2) sulphite and edetate are added into the water for injection of amount of preparation 20%, stirs to dissolve, into the liquid 0.2% needle-use activated carbon, stirring and adsorbing 30 minutes, filtering is added;
(3) liquid obtained by step (1) and step (2) is mixed, adds the water for injection of amount of preparation 50%, mixed, optional uses acid In 5.0 ~ 7.0 ranges, benefit adds to the full amount of water for injection the pH of alkali conditioning agent regulating liquid medicine;
(4) prepare after the completion of liquid by aseptic filtration be sent into embedding between after aseptic filtration again, liquid is filled into cleaning and is gone out In bacterium ampoule bottle, carry out nitrogen filling after seal, carry out flowing steam sterilization processing after, leak detection to get.
9. netilmicin sulfate injection according to claim 8 becomes per 1ml groups:The U of netilmicin sulfate 2 ~ 100,000, nothing 2 ~ 9mg of water sodium sulfite, 0.2 ~ 1mg of L-cysteine, natrium adetate or 0.1 ~ 0.6mg of mosatil and water for injection Add to 1ml in right amount.
10. netilmicin sulfate injection according to claim 8 becomes per 1ml groups:The U of netilmicin sulfate 2 ~ 100,000, nothing 2 ~ 9mg of water sodium sulfite, 0.2 ~ 1mg of L-cysteine, 0.1 ~ 0.6mg of natrium adetate and water for injection add to 1ml in right amount.
11. netilmicin sulfate injection according to claim 8 becomes per 1ml groups:The U of netilmicin sulfate 3 ~ 80,000, nothing 2 ~ 5mg of water sodium sulfite, 0.2 ~ 0.6mg of L-cysteine, 0.1 ~ 0.5mg of natrium adetate and water for injection add in right amount 1ml。
12. netilmicin sulfate injection according to claim 8 becomes per 1ml groups:It is 50,000 U of netilmicin sulfate, anhydrous Sodium sulfite 3mg, L-cysteine 0.4mg, natrium adetate 0.2mg and water for injection add to 1ml in right amount.
13. netilmicin sulfate injection according to claim 8, used in water for injection water temperature at 40 DEG C or less.
14. netilmicin sulfate injection according to claim 8, flowing steam sterilization processing is at 100 DEG C in step (4) Flowing steam sterilization is handled 30 minutes.
15. test right requires method of the netilmicin sulfate injection in relation to substance of any one of 8-14, include the following steps:
Precision measurement netilmicin sulfate injection is appropriate, is quantitatively diluted and is made in every 1ml containing about Netilmicin 2.0mg's with water Solution, as test solution;Measure test solution it is appropriate, quantitatively diluted with water be made it is each containing about Netilmicin in every 1ml The solution of 25 μ g, 50 μ g, 100 μ g, as a contrast solution (1), (2), (3);According to four general rules 0512 of version Chinese Pharmacopoeia in 2015 High effective liquid chromatography for measuring is filler with octadecyl silane;Include 0.02mol/L tartaric acid with 0.2mol/L Both trifluoroacetic acid solution-methanol is with volume ratio 84:16 be mobile phase, and flow velocity is 0.5ml per minute;Use Evaporative light scattering detector Device detects;100 °C of drift tube temperature, flow rate of carrier gas are 2.6L per minute;Take Netilmicin standard items and Etimicin reference substance Each appropriate, being dissolved in water and diluting is made in every 1ml the respectively mixed solution containing 0.2mg, takes 20 μ l injection liquid chromatographs, record The separating degree at chromatogram, Netilmicin peak and Etimicin peak should be greater than 1.2;Contrast solution (1), (2), (3) each 20 μ are taken immediately L is injected separately into liquid chromatograph, records chromatogram, in terms of the logarithm of contrast solution concentration and the logarithm of corresponding peak area Equation of linear regression is calculated, related coefficient (r) should be not less than 0.99;It is another to take 20 μ l injection liquid chromatographs of test solution, record Chromatogram is to 2 times of principal component peak retention time.
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