WO2022227115A1 - Preparation method for sisomicin sulfate sterile powder injection for injection - Google Patents
Preparation method for sisomicin sulfate sterile powder injection for injection Download PDFInfo
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- WO2022227115A1 WO2022227115A1 PCT/CN2021/093190 CN2021093190W WO2022227115A1 WO 2022227115 A1 WO2022227115 A1 WO 2022227115A1 CN 2021093190 W CN2021093190 W CN 2021093190W WO 2022227115 A1 WO2022227115 A1 WO 2022227115A1
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- Prior art keywords
- injection
- sisomicin sulfate
- preparation
- sterile powder
- sisomicin
- Prior art date
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- 238000002347 injection Methods 0.000 title claims abstract description 66
- 239000007924 injection Substances 0.000 title claims abstract description 66
- BWRBVBFLFQKBPT-UHFFFAOYSA-N (2-nitrophenyl)methanol Chemical compound OCC1=CC=CC=C1[N+]([O-])=O BWRBVBFLFQKBPT-UHFFFAOYSA-N 0.000 title claims abstract description 58
- 229960001435 sisomicin sulfate Drugs 0.000 title claims abstract description 58
- 239000000843 powder Substances 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 230000001954 sterilising effect Effects 0.000 claims abstract description 10
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 9
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 9
- 239000013078 crystal Substances 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000008025 crystallization Effects 0.000 claims abstract description 7
- 239000008215 water for injection Substances 0.000 claims abstract description 7
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 5
- 239000011261 inert gas Substances 0.000 claims abstract description 4
- 238000004659 sterilization and disinfection Methods 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 6
- 239000001509 sodium citrate Substances 0.000 claims description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 5
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 4
- URWAJWIAIPFPJE-UHFFFAOYSA-N Rickamicin Natural products O1CC(O)(C)C(NC)C(O)C1OC1C(O)C(OC2C(CC=C(CN)O2)N)C(N)CC1N URWAJWIAIPFPJE-UHFFFAOYSA-N 0.000 claims description 3
- 229930192786 Sisomicin Natural products 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 229960005456 sisomicin Drugs 0.000 claims description 3
- URWAJWIAIPFPJE-YFMIWBNJSA-N sisomycin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(CN)O2)N)[C@@H](N)C[C@H]1N URWAJWIAIPFPJE-YFMIWBNJSA-N 0.000 claims description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- 229930182817 methionine Natural products 0.000 claims description 2
- 235000006109 methionine Nutrition 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 2
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- 238000011146 sterile filtration Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 238000001816 cooling Methods 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 4
- 238000003860 storage Methods 0.000 abstract description 4
- 238000004090 dissolution Methods 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 230000007774 longterm Effects 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 3
- 229930182566 Gentamicin Natural products 0.000 description 3
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 229960002518 gentamicin Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 description 2
- 241000607720 Serratia Species 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960000707 tobramycin Drugs 0.000 description 2
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 2
- 108010077805 Bacterial Proteins Proteins 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229940126574 aminoglycoside antibiotic Drugs 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
Definitions
- the invention relates to the preparation of sterile powder injections, in particular to a preparation method of sisomicin sulfate sterile powder injections for injection.
- Sisomicin sulfate is a new aminoglycoside antibiotic used to treat infections caused by Staphylococcus, Escherichia coli, Proteus, Pseudomonas aeruginosa, Serratia, Klebsiella pneumoniae and other bacteria.
- sisomicin sulfate plays an antibacterial effect by hindering the synthesis of bacterial sensitive proteins.
- the bacteria have broad and strong biological activities, and the antibacterial spectrum is similar to that of gentamicin.
- sisomicin sulfate is effective against gram-negative bacteria such as Staphylococcus aureus and Escherichia coli, Klebsiella, Proteus, Enterobacter, Pseudomonas aeruginosa, Shigella spp.
- the antibacterial effect of Pseudomonas aeruginosa is stronger than that of gentamicin and similar to that of tobramycin; the effect on Serratia is lower than that of gentamicin, but higher than that of tobramycin.
- sisomicin sulfate is unstable to heat and oxidized when exposed to air for a long time, unqualified phenomena such as clarity and color (yellowish) are prone to occur during production and storage, thus affecting its product quality.
- the Chinese invention patent with the announcement number of CN1058362236B discloses a sisomicin sulfate freeze-dried powder injection and a preparation method thereof. Freeze-dried. However, because the freeze-drying method is to quickly freeze the sterile solution of the drug, then slowly heat it to sublime the water in the solution to prepare a powder injection. The prepared powder injection is mainly amorphous crystals, so there are many degraded substances and product stability. poor, etc. At the same time, due to the large electricity consumption of the freeze dryer, the production cost of this method is relatively high.
- the present invention provides a preparation method of sisomicin sulfate sterile powder injection for injection.
- a preparation method of sisomicin sulfate sterile powder injection for injection which comprises the following steps: under the protection of inactive gas, taking water for injection, adding antioxidants to dissolve, cooling the temperature to below 20 DEG C, adding sisomicin sulfate to dissolve, adjusting The pH value reaches 5.0-5.5, after decolorization and sterilization filtration, the temperature is lowered to 0-5°C, and ethanol is slowly added dropwise for solvent crystallization, and the obtained crystals are dried at low temperature to obtain the sisomicin sulfate sterile powder for injection. injection.
- the antioxidant is at least one of cysteine, methionine, sodium bisulfite and sodium metabisulfite.
- the weight ratio of the sisomicin sulfate to the antioxidant is 100: 0.5-2; the weight-volume ratio of the sisomicin sulfate to the water for injection is 1 g: 4-7 mL.
- a 0.22 ⁇ m primary sterilization filter is used for filtration, and then a 0.22 ⁇ m secondary terminal sterilization filtration is used.
- the low temperature drying is low temperature vacuum drying.
- the temperature of the low-temperature vacuum drying is less than or equal to 28°C, and the pressure is 0.08-0.1 MPa.
- the adjustment of the pH value is performed by using an alkaline aqueous solution containing sodium citrate.
- the crystals need to be washed with ethanol.
- sisomicin sulfate sterile powder injection for injection also needs to be aseptically subpackaged.
- the temperature of the solvent crystallization is less than or equal to 0°C.
- the present invention prepares the sisomicin sulfate sterile powder injection for injection by selecting suitable process conditions and adopting the solvent crystallization method, and the obtained product has good stability, less impurity content, high safety, and excellent resolubility, which is favorable for long-term storage;
- inert gas is always used for protection in the production process, and after adding antioxidant, it is cooled to a lower temperature to dissolve sisomicin sulfate, sterilize and crystallize, and can effectively reduce the degradation of sisomicin sulfate;
- the invention adopts the alkaline solution containing sodium citrate to adjust the pH value, which can effectively maintain the stability of the pH value of the system, thereby inhibiting the degradation of sisomicin sulfate; at the same time, in the preparation process, the sodium citrate can also play a certain role. antioxidant effect;
- the invention adopts the low-temperature vacuum drying method to dry the obtained sisomicin sulfate crystal, suppresses the thermal degradation phenomenon of sisomicin sulfate, reduces energy consumption and production cost, and is suitable for industrialized production.
- Embodiment 1 A kind of preparation method of sisomicin sulfate sterile powder injection for injection
- the present embodiment is a preparation method of sisomicin sulfate sterile powder injection for injection, and the specific preparation process includes the following steps performed in sequence:
- the filtrate is filtered through a 0.22 ⁇ m primary sterilization filter, and then passed through a 0.22 ⁇ m secondary terminal sterilization filter to effectively remove bacterial microorganisms.
- the obtained sterile medicine Under the protection of nitrogen, the liquid was stirred and cooled to 0 °C (to ensure no freezing, this cooling was recorded as the second cooling), and anhydrous ethanol was slowly added dropwise at a rate of 250mL/h (the rate of addition should not be too fast, but Not limited to the rate of addition), dropwise added until a small amount of crystals appeared, then stopped dripping, and then cooled to -5°C at a cooling rate of 5°C/h (recorded as the third cooling), stirred and crystallized at -5°C for 5h, Filtered, washed 3 times with 10 mL of absolute ethanol, and then vacuum-dried for 5 h at a temperature of 25 °C and a pressure of 0.1 MPa to remove residual solvent, and then aseptically packaged according to the
- the nitrogen in this embodiment can also be replaced by other inert gas, such as argon, etc., but considering the production cost, nitrogen is generally used.
- Embodiment 2 ⁇ 6 Preparation method of sisomicin sulfate sterile powder injection for injection
- Embodiments 2-6 are respectively a kind of preparation method of sisomicin sulfate aseptic powder injection for injection, their steps are basically the same as those of embodiment 1, and the difference is only in the amount of raw materials and process parameters. For details, please refer to the details. Table 1:
- the sisomicin sulfate sterile powder for injection prepared in Examples 1 to 6 has good stability, high content of the main drug, few impurities, and excellent resolubility.
- Comparative Examples 1 to 6 are the comparative tests of the preparation process of sisomicin sulfate sterile powder injection for injection in Example 1 [specification 0.1g (calculated by sisomicin)], and the differences are only as follows:
- the dissolution temperature of sisomicin sulfate in Comparative Example 1 was 30°C;
- the temperature of solvent crystallization in Comparative Example 4 was 5°C;
- the temperature of vacuum drying in Comparative Example 5 was 35°C;
- Comparative Example 7 Sisomicin sulfate freeze-dried powder injection was prepared according to the preparation method disclosed in Example 1 of Chinese Invention Patent No. CN1058362236B.
- the stability of the sisomicin sulfate for injection sterile powder injection prepared in Examples 1 to 6 of the present invention is better than the sterile sisomicin sulfate for injection prepared in Comparative Examples 1 to 7. Powder injection.
- the sisomicin sulfate sterile powder for injection prepared in Examples 1 to 6 has lower content of related substances and better redissolving properties. It is illustrated that the process parameters of the present invention are more conducive to the preparation and storage of the sisomicin sulfate sterile powder injection for injection.
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
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- Oil, Petroleum & Natural Gas (AREA)
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- Communicable Diseases (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the technical field of medicine preparation, and provides a preparation method for a sisomicin sulfate sterile powder injection for injection. The preparation method comprises: under the protection of inert gas, taking water for injection, adding an antioxidant for dissolution, then cooling down to 20°C or below, adding sisomicin sulfate for dissolution, adjusting a pH value to 5.0-5.5, then decoloring, sterilizing and filtering, cooling down to 0-5°C, slowly dropping ethanol for solvent crystallization, and drying obtained crystals to obtain the sisomicin sulfate sterile powder injection for injection. According to the present invention, the sisomicin sulfate sterile powder injection for injection is prepared by selecting proper process conditions and using a solvent crystallization method, and the obtained product is good in stability, low in impurity content, high in safety, excellent in resolubility, and beneficial to long-term storage.
Description
本发明涉及无菌粉针剂的制备，尤其涉及一种注射用硫酸西索米星无菌粉针剂的制备方法。The invention relates to the preparation of sterile powder injections, in particular to a preparation method of sisomicin sulfate sterile powder injections for injection.
硫酸西索米星是一种新型氨基糖苷类抗生素，用于治疗葡萄球菌、大肠杆菌、变形杆菌、绿脓杆菌、沙雷氏菌、克雷伯肺炎杆菌等病菌引起的感染。Sisomicin sulfate is a new aminoglycoside antibiotic used to treat infections caused by Staphylococcus, Escherichia coli, Proteus, Pseudomonas aeruginosa, Serratia, Klebsiella pneumoniae and other bacteria.
硫酸西索米星的作用机制是与细菌核糖体30S亚单位结合，抑制细菌蛋白质的合成，硫酸西索米星就是通过阻碍细菌敏感蛋白质的合成而起抗菌作用，其对革兰氏阳、阴性菌均具有广而强的生物学活性，抗菌谱与庆大霉素相似。体外研究显示，硫酸西索米星对金黄色葡萄球菌和大肠埃希菌、克雷白杆菌、变形杆菌、肠杆菌属、铜绿假单胞菌、痢疾杆菌等革兰氏阴性菌均有效；对铜绿假单胞菌的抗菌作用较庆大霉素强，与妥布霉素相近；对沙雷杆菌的作用低于庆大霉素，但高于妥布霉素。The mechanism of action of sisomicin sulfate is to combine with the 30S subunit of bacterial ribosome to inhibit the synthesis of bacterial proteins. Sisomicin sulfate plays an antibacterial effect by hindering the synthesis of bacterial sensitive proteins. The bacteria have broad and strong biological activities, and the antibacterial spectrum is similar to that of gentamicin. In vitro studies have shown that sisomicin sulfate is effective against gram-negative bacteria such as Staphylococcus aureus and Escherichia coli, Klebsiella, Proteus, Enterobacter, Pseudomonas aeruginosa, Shigella spp. The antibacterial effect of Pseudomonas aeruginosa is stronger than that of gentamicin and similar to that of tobramycin; the effect on Serratia is lower than that of gentamicin, but higher than that of tobramycin.
由于硫酸西索米星对热不稳定，且长时间暴露在空气中会氧化，在生产和贮存过程中易出现澄清度与颜色(偏黄)等不合格现象，从而影响其产品质量。Because sisomicin sulfate is unstable to heat and oxidized when exposed to air for a long time, unqualified phenomena such as clarity and color (yellowish) are prone to occur during production and storage, thus affecting its product quality.
公告号为CN1058362236B的中国发明专利中公开了一种硫酸西索米星冻干粉针及其制备方法，是以硫酸西索米星、甘露醇、聚乙二醇、pH调节剂为原料，经冷冻干燥制得。但由于冻干法是将药品的无菌溶液快速冻结后，慢慢加热使溶液中水分升华制备粉针剂，制得的粉针剂以无定形晶体为主，因此存在降解物质较多、产品稳定性较差等问题。同时由于冻干机用电量较 大，导致该方法生产成本较高。The Chinese invention patent with the announcement number of CN1058362236B discloses a sisomicin sulfate freeze-dried powder injection and a preparation method thereof. Freeze-dried. However, because the freeze-drying method is to quickly freeze the sterile solution of the drug, then slowly heat it to sublime the water in the solution to prepare a powder injection. The prepared powder injection is mainly amorphous crystals, so there are many degraded substances and product stability. poor, etc. At the same time, due to the large electricity consumption of the freeze dryer, the production cost of this method is relatively high.
发明内容SUMMARY OF THE INVENTION
针对上述问题，本发明提供一种注射用硫酸西索米星无菌粉针剂的制备方法。In view of the above problems, the present invention provides a preparation method of sisomicin sulfate sterile powder injection for injection.
为实现上述目的，本发明所采用的技术方案为：For achieving the above object, the technical scheme adopted in the present invention is:
一种注射用硫酸西索米星无菌粉针剂的制备方法，是在非活性气体保护下，取注射用水加入抗氧剂溶解后，降温至20℃以下，加入硫酸西索米星溶解，调节pH值至5.0～5.5，经脱色、除菌过滤后，降温至0～5℃，缓慢滴加乙醇进行溶媒结晶，所得晶体经低温干燥，即得所述注射用硫酸西索米星无菌粉针剂。A preparation method of sisomicin sulfate sterile powder injection for injection, which comprises the following steps: under the protection of inactive gas, taking water for injection, adding antioxidants to dissolve, cooling the temperature to below 20 DEG C, adding sisomicin sulfate to dissolve, adjusting The pH value reaches 5.0-5.5, after decolorization and sterilization filtration, the temperature is lowered to 0-5°C, and ethanol is slowly added dropwise for solvent crystallization, and the obtained crystals are dried at low temperature to obtain the sisomicin sulfate sterile powder for injection. injection.
进一步的，所述抗氧剂为半胱氨酸、甲硫氨酸、亚硫酸氢钠及焦亚硫酸钠中的至少一种。Further, the antioxidant is at least one of cysteine, methionine, sodium bisulfite and sodium metabisulfite.
进一步的，所述硫酸西索米星与抗氧剂的重量比为100：0.5～2；所述硫酸西索米星与注射用水的重量体积比为1g：4～7mL。Further, the weight ratio of the sisomicin sulfate to the antioxidant is 100: 0.5-2; the weight-volume ratio of the sisomicin sulfate to the water for injection is 1 g: 4-7 mL.
进一步的，所述除菌过滤是先利用0.22μm一次除菌滤器过滤，再利用0.22μm二次终端除菌过滤。Further, in the sterilization filtration, firstly, a 0.22 μm primary sterilization filter is used for filtration, and then a 0.22 μm secondary terminal sterilization filtration is used.
进一步的，所述低温干燥为低温真空干燥。Further, the low temperature drying is low temperature vacuum drying.
进一步的，所述低温真空干燥的温度≤28℃、压力为0.08～0.1MPa。Further, the temperature of the low-temperature vacuum drying is less than or equal to 28°C, and the pressure is 0.08-0.1 MPa.
进一步的，所述调节pH值是利用含有枸橼酸钠的碱性水溶液进行调节。Further, the adjustment of the pH value is performed by using an alkaline aqueous solution containing sodium citrate.
进一步的，所述溶媒结晶后且低温干燥前，所述晶体还需使用乙醇洗涤。Further, after the solvent is crystallized and before drying at low temperature, the crystals need to be washed with ethanol.
进一步的，所述注射用硫酸西索米星无菌粉针剂还需进行无菌分装。Further, the sisomicin sulfate sterile powder injection for injection also needs to be aseptically subpackaged.
进一步的，所述溶媒结晶的温度≤0℃。Further, the temperature of the solvent crystallization is less than or equal to 0°C.
本发明的注射用硫酸西索米星无菌粉针剂的制备方法的有益效果为：The beneficial effects of the preparation method of the sisomicin sulfate sterile powder injection for injection of the present invention are:
本发明通过选用合适的工艺条件，采用溶媒结晶法制备注射用硫酸西索米星无菌粉针剂，所得产品稳定性好、杂质含量少，安全性高，复溶性优良，利于长期储存；The present invention prepares the sisomicin sulfate sterile powder injection for injection by selecting suitable process conditions and adopting the solvent crystallization method, and the obtained product has good stability, less impurity content, high safety, and excellent resolubility, which is favorable for long-term storage;
本发明在生产过程始终使用惰性气体进行保护，并在加入抗氧剂后降温至较低温度溶解硫酸西索米星、除菌、析晶，能够有效减少硫酸西索米星降解；In the present invention, inert gas is always used for protection in the production process, and after adding antioxidant, it is cooled to a lower temperature to dissolve sisomicin sulfate, sterilize and crystallize, and can effectively reduce the degradation of sisomicin sulfate;
本发明采用含有枸橼酸钠的碱性溶液调节pH值，能够有效维持体系pH值的稳定性，进而抑制硫酸西索米星降解；同时在制备过程中，枸橼酸钠还能够起到一定的抗氧化作用；The invention adopts the alkaline solution containing sodium citrate to adjust the pH value, which can effectively maintain the stability of the pH value of the system, thereby inhibiting the degradation of sisomicin sulfate; at the same time, in the preparation process, the sodium citrate can also play a certain role. antioxidant effect;
本发明采用低温真空干燥的方式对所得硫酸西索米星晶体进行干燥，抑制了硫酸西索米星受热降解现象，同时也降低了能耗，降低了生产成本，适于工业化生产。The invention adopts the low-temperature vacuum drying method to dry the obtained sisomicin sulfate crystal, suppresses the thermal degradation phenomenon of sisomicin sulfate, reduces energy consumption and production cost, and is suitable for industrialized production.
下面对本发明实施例中的技术方案进行清楚、完整地描述。在下面的描述中阐述了很多具体细节以便于充分理解本发明，但是本发明还可以采用其他不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似推广，因此本发明不受下面公开的具体实施例的限制。The technical solutions in the embodiments of the present invention will be clearly and completely described below. Many specific details are set forth in the following description to facilitate a full understanding of the present invention, but the present invention can also be implemented in other ways different from those described herein, and those skilled in the art can do so without departing from the connotation of the present invention. Similar promotion, therefore, the present invention is not limited by the specific embodiments disclosed below.
实施例1 一种注射用硫酸西索米星无菌粉针剂的制备方法Embodiment 1 A kind of preparation method of sisomicin sulfate sterile powder injection for injection
本实施例为一种注射用硫酸西索米星无菌粉针剂的制备方法，具体制备过程包括依次进行的以下步骤：The present embodiment is a preparation method of sisomicin sulfate sterile powder injection for injection, and the specific preparation process includes the following steps performed in sequence:
取注射用水煮沸放冷备用；Boil water for injection and let it cool for later use;
在氮气保护下，取500mL煮沸后的注射用水，加入1g的L-半胱氨酸搅拌充分溶解后，采用0.45μm的微孔滤膜过滤除去不溶物质和部分残留细菌微生物，降温至15℃(记作第一次降温)，加入100g硫酸西索米星搅拌溶解，使用少量含有0.1mol/L枸橼酸钠和0.1mol/L氢氧化钠的水溶液调节pH值至5.5，整个过程始终维持体系温度为15℃，然后加入2g药用活性炭，15℃搅拌脱色30min，过滤，滤液经0.22μm一次除菌滤器过滤，再经0.22μm二次终端除菌过滤，有效去除细菌微生物，所得无菌药液再在氮气保护下，搅拌降温至0℃(保证无结冰，此次降温记作第二次降温)，缓慢滴加无水乙醇，滴加速度为250mL/h(滴加速度不可过快，但并不限于该滴加速度)，滴加至出现少量晶体后停止滴加，然后以5℃/h的降温速度降温至-5℃(记作第三次降温)，-5℃搅拌析晶5h，过滤，使用10mL无水乙醇洗涤3次，再置于温度为25℃、压力为0.1MPa的条件下进行真空干燥5h，除去残留溶剂，再按所需规格进行无菌分装【本实施例规格为0.1g(以西索米星计)】，即得注射用硫酸西索米星无菌粉针剂。Under nitrogen protection, take 500 mL of boiled water for injection, add 1 g of L-cysteine and stir to fully dissolve, use a 0.45 μm microporous membrane to filter to remove insoluble substances and some residual bacterial microorganisms, and cool to 15 ° C ( Recorded as the first cooling), add 100g of sisomicin sulfate and stir to dissolve, use a small amount of aqueous solution containing 0.1mol/L sodium citrate and 0.1mol/L sodium hydroxide to adjust the pH value to 5.5, and maintain the system throughout the process. The temperature is 15°C, then 2g of medicinal activated carbon is added, stirred at 15°C for 30 minutes, and filtered. The filtrate is filtered through a 0.22 μm primary sterilization filter, and then passed through a 0.22 μm secondary terminal sterilization filter to effectively remove bacterial microorganisms. The obtained sterile medicine Under the protection of nitrogen, the liquid was stirred and cooled to 0 °C (to ensure no freezing, this cooling was recorded as the second cooling), and anhydrous ethanol was slowly added dropwise at a rate of 250mL/h (the rate of addition should not be too fast, but Not limited to the rate of addition), dropwise added until a small amount of crystals appeared, then stopped dripping, and then cooled to -5°C at a cooling rate of 5°C/h (recorded as the third cooling), stirred and crystallized at -5°C for 5h, Filtered, washed 3 times with 10 mL of absolute ethanol, and then vacuum-dried for 5 h at a temperature of 25 °C and a pressure of 0.1 MPa to remove residual solvent, and then aseptically packaged according to the required specifications [Specifications in this example] 0.1g (calculated as sisomicin)], that is, sisomicin sulfate sterile powder injection for injection.
本实施例中的氮气也可使用其它惰性气体代替，比如氩气等，但考虑到生产成本，一般都使用氮气。The nitrogen in this embodiment can also be replaced by other inert gas, such as argon, etc., but considering the production cost, nitrogen is generally used.
实施例2～6 注射用硫酸西索米星无菌粉针剂的制备方法Embodiment 2～6 Preparation method of sisomicin sulfate sterile powder injection for injection
实施例2～6分别为一种注射用硫酸西索米星无菌粉针剂的制备方法，它们的步骤与实施例1基本相同，不同之处仅在于原料用量及工艺参数的不同，具体详见表1：Embodiments 2-6 are respectively a kind of preparation method of sisomicin sulfate aseptic powder injection for injection, their steps are basically the same as those of embodiment 1, and the difference is only in the amount of raw materials and process parameters. For details, please refer to the details. Table 1:
表1 实施例2～6中各项工艺参数一览表Table 1 List of various process parameters in Examples 2 to 6
实施例2～6其它部分的内容，与实施例1相同。The contents of other parts of Examples 2 to 6 are the same as those of Example 1.
实施例1～6制备的注射用硫酸西索米星无菌粉针剂稳定性好、主药含量高、杂质少，复溶性优良。The sisomicin sulfate sterile powder for injection prepared in Examples 1 to 6 has good stability, high content of the main drug, few impurities, and excellent resolubility.
实验例1 注射用硫酸西索米星无菌粉针剂的性能测定Experimental Example 1 Determination of performance of sisomicin sulfate sterile powder for injection
对比例1～6为实施例1中注射用硫酸西索米星无菌粉针针剂【规格0.1g(以西索米星计)】的制备过程的对比试验，区别仅在于：Comparative Examples 1 to 6 are the comparative tests of the preparation process of sisomicin sulfate sterile powder injection for injection in Example 1 [specification 0.1g (calculated by sisomicin)], and the differences are only as follows:
对比例1中硫酸西索米星的溶解温度为30℃；The dissolution temperature of sisomicin sulfate in Comparative Example 1 was 30°C;
对比例2中pH值调节为4.5；In Comparative Example 2, the pH value was adjusted to 4.5;
对比例3中滴加乙醇时，体系温度为10℃；When ethanol was added dropwise in Comparative Example 3, the temperature of the system was 10°C;
对比例4中溶媒结晶的温度为5℃；The temperature of solvent crystallization in Comparative Example 4 was 5°C;
对比例5中真空干燥的温度为35℃；The temperature of vacuum drying in Comparative Example 5 was 35°C;
对比例6中不添加抗氧剂；No antioxidant was added in Comparative Example 6;
对比例7按照公告号为CN1058362236B的中国发明专利实施例1中公开的制备方法制备硫酸西索米星冻干粉针剂。Comparative Example 7 Sisomicin sulfate freeze-dried powder injection was prepared according to the preparation method disclosed in Example 1 of Chinese Invention Patent No. CN1058362236B.
由于注射用硫酸西索米星在药典中规定的pH值为3.0～5.5，因此这里不再增设pH值大于5.5的对比例。Since the pH value of sisomicin sulfate for injection specified in the Pharmacopoeia is 3.0 to 5.5, a comparative example with a pH value greater than 5.5 is not added here.
取实施例1～6和对比例1～6中制得的注射用硫酸西索米星无菌粉针剂及对比例7制备的硫酸西索米星冻干粉针剂，分别于40±2℃、RH75±5％的条件下放置12个月，期间分别于第1、3、6、9和12个月取样，按照《中国药典》(2015版第二部)中规定的检测项目及方法进行检测，并与0天数据比较，具体检测结果见下表：Take the sisomicin sulfate sterile powder for injection prepared in Examples 1-6 and Comparative Examples 1-6 and the sisomicin sulfate freeze-dried powder for injection prepared in Comparative Example 7, respectively, at 40±2° C., Under the condition of RH75±5% for 12 months, samples were taken in the 1st, 3rd, 6th, 9th and 12th months respectively, and the test was carried out according to the test items and methods specified in the "Chinese Pharmacopoeia" (2015 Edition Part 2). , and compared with the 0-day data, the specific test results are shown in the following table:
表2 加速试验检测结果一览表Table 2 List of test results of accelerated test
由表2可以看出，本发明实施例1～6制得的注射用硫酸西索米星无菌粉针剂的稳定性优于对比例1～7制得的注射用硫酸西索米星无菌粉针剂。且实施例1～6制得的注射用硫酸西索米星无菌粉针剂中的有关物质含量更低，复溶性更好。说明本发明的工艺参数更利于注射用硫酸西索米星无菌粉针剂的制备和储存。As can be seen from Table 2, the stability of the sisomicin sulfate for injection sterile powder injection prepared in Examples 1 to 6 of the present invention is better than the sterile sisomicin sulfate for injection prepared in Comparative Examples 1 to 7. Powder injection. In addition, the sisomicin sulfate sterile powder for injection prepared in Examples 1 to 6 has lower content of related substances and better redissolving properties. It is illustrated that the process parameters of the present invention are more conducive to the preparation and storage of the sisomicin sulfate sterile powder injection for injection.
显然，所描述的实施例仅仅是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。Obviously, the described embodiments are only some, but not all, embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.
Claims (10)
- 一种注射用硫酸西索米星无菌粉针剂的制备方法，其特征在于，所述制备方法是在非活性气体保护下，取注射用水加入抗氧剂溶解后，降温至20℃以下，加入硫酸西索米星溶解，调节pH值至5.0～5.5，经脱色、除菌过滤后，降温至0～5℃，缓慢滴加乙醇进行溶媒结晶，所得晶体经干燥，即得所述注射用硫酸西索米星无菌粉针剂。A preparation method of sisomicin sulfate sterile powder injection for injection, characterized in that, under the protection of inert gas, water for injection is added with an antioxidant to dissolve, and the temperature is lowered to below 20° C. Dissolve sisomicin sulfate, adjust the pH value to 5.0-5.5, decolorize, sterilize and filter, cool down to 0-5°C, slowly add ethanol dropwise for solvent crystallization, and dry the obtained crystals to obtain the sulfuric acid for injection. Sisomicin sterile powder for injection.
- 根据权利要求1所述的注射用硫酸西索米星无菌粉针剂的制备方法，其特征在于，所述抗氧剂为半胱氨酸、甲硫氨酸、亚硫酸氢钠及焦亚硫酸钠中的至少一种。The preparation method of sisomicin sulfate sterile powder for injection according to claim 1, is characterized in that, described antioxidant is in cysteine, methionine, sodium bisulfite and sodium metabisulfite at least one of.
- 根据权利要求1或2所述的注射用硫酸西索米星无菌粉针剂的制备方法，其特征在于，所述硫酸西索米星与抗氧剂的重量比为100：0.5～2；所述硫酸西索米星与注射用水的重量体积比为1g：4～7mL。The preparation method of sisomicin sulfate sterile powder injection for injection according to claim 1 or 2, characterized in that, the weight ratio of the sisomicin sulfate to antioxidant is 100:0.5-2; The weight-to-volume ratio of sisomicin sulfate to water for injection is 1 g: 4-7 mL.
- 根据权利要求1或2所述的注射用硫酸西索米星无菌粉针剂的制备方法，其特征在于，所述除菌过滤是先利用0.22μm一次除菌滤器过滤，再利用0.22μm二次终端除菌过滤。The preparation method of sisomicin sulfate aseptic powder for injection according to claim 1 or 2, characterized in that, the sterilization filtration is to first use a 0.22 μm sterilization filter to filter, and then use a 0.22 μm secondary sterilization filter. Terminal sterile filtration.
- 根据权利要求1或2所述的注射用硫酸西索米星无菌粉针剂的制备方法，其特征在于，所述干燥为真空干燥。The preparation method of sisomicin sulfate sterile powder for injection according to claim 1 or 2, wherein the drying is vacuum drying.
- 根据权利要求5所述的注射用硫酸西索米星无菌粉针剂的制备方法，其特征在于，所述真空干燥的温度≤28℃、压力为0.08～0.1MPa。The method for preparing sisomicin sulfate sterile powder for injection according to claim 5, wherein the temperature of the vacuum drying is ≤28°C and the pressure is 0.08-0.1MPa.
- 根据权利要求1、2或6所述的注射用硫酸西索米星无菌粉针剂的制备方法，其特征在于，所述调节pH值是利用含有枸橼酸钠的碱性水溶液进行调节。The preparation method of sisomicin sulfate sterile powder for injection according to claim 1, 2 or 6, characterized in that, the pH value is adjusted by utilizing an alkaline aqueous solution containing sodium citrate.
- 根据权利要求1、2或6所述的注射用硫酸西索米星无菌粉针剂的制备方 法，其特征在于，所述溶媒结晶后且干燥前，所述晶体还需使用乙醇洗涤。The preparation method of sisomicin sulfate sterile powder for injection according to claim 1, 2 or 6, is characterized in that, after described solvent crystallization and before drying, described crystal also needs to use ethanol washing.
- 根据权利要求1、2或6所述的注射用硫酸西索米星无菌粉针剂的制备方法，其特征在于，所述注射用硫酸西索米星无菌粉针剂还需进行无菌分装。The preparation method of sisomicin sulfate aseptic powder for injection according to claim 1, 2 or 6, it is characterized in that, described sisomicin sulfate aseptic powder for injection also needs to carry out aseptic subpackaging .
- 根据权利要求1、2或6所述的注射用硫酸西索米星无菌粉针剂的制备方法，其特征在于，所述溶媒结晶的温度≤0℃。The preparation method of sisomicin sulfate sterile powder for injection according to claim 1, 2 or 6, wherein the temperature of the solvent crystallization is less than or equal to 0°C.
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