CN114246832A - Tedizolid phosphate for injection and preparation method thereof - Google Patents
Tedizolid phosphate for injection and preparation method thereof Download PDFInfo
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- CN114246832A CN114246832A CN202111677379.6A CN202111677379A CN114246832A CN 114246832 A CN114246832 A CN 114246832A CN 202111677379 A CN202111677379 A CN 202111677379A CN 114246832 A CN114246832 A CN 114246832A
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- 229960003947 tedizolid phosphate Drugs 0.000 title claims abstract description 54
- QCGUSIANLFXSGE-GFCCVEGCSA-N tedizolid phosphate Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](COP(O)(O)=O)C2)=O)F)=N1 QCGUSIANLFXSGE-GFCCVEGCSA-N 0.000 title claims abstract description 54
- 238000002347 injection Methods 0.000 title claims abstract description 37
- 239000007924 injection Substances 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 239000000243 solution Substances 0.000 claims abstract description 90
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 84
- 238000000034 method Methods 0.000 claims abstract description 29
- 238000004108 freeze drying Methods 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000008215 water for injection Substances 0.000 claims abstract description 27
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 22
- 229930195725 Mannitol Natural products 0.000 claims abstract description 22
- 239000000594 mannitol Substances 0.000 claims abstract description 22
- 235000010355 mannitol Nutrition 0.000 claims abstract description 22
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims abstract description 20
- 229930006000 Sucrose Natural products 0.000 claims abstract description 20
- 239000005720 sucrose Substances 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 239000003223 protective agent Substances 0.000 claims abstract description 13
- 230000002378 acidificating effect Effects 0.000 claims abstract description 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 28
- 230000001954 sterilising effect Effects 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 238000011146 sterile filtration Methods 0.000 claims description 14
- 238000012371 Aseptic Filling Methods 0.000 claims description 12
- 238000011049 filling Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 229910001220 stainless steel Inorganic materials 0.000 claims description 7
- 239000010935 stainless steel Substances 0.000 claims description 7
- 238000003860 storage Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 2
- 229960004793 sucrose Drugs 0.000 description 16
- 238000011068 loading method Methods 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 230000008569 process Effects 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- -1 polyethylene-tetrafluoroethylene Polymers 0.000 description 10
- 238000011179 visual inspection Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 8
- 238000005259 measurement Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229920005557 bromobutyl Polymers 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000013339 in-process testing Methods 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 238000007689 inspection Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 238000012856 packing Methods 0.000 description 5
- 238000005096 rolling process Methods 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- 238000012795 verification Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 3
- 241000194032 Enterococcus faecalis Species 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- XFALPSLJIHVRKE-GFCCVEGCSA-N tedizolid Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)=N1 XFALPSLJIHVRKE-GFCCVEGCSA-N 0.000 description 2
- MIXXTDJJUKULIC-LLVKDONJSA-N (5R)-3-[3-fluoro-4-[6-(2H-tetrazol-5-yl)pyridin-3-yl]phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one Chemical compound OC[C@H]1CN(C(=O)O1)c1ccc(c(F)c1)-c1ccc(nc1)-c1nn[nH]n1 MIXXTDJJUKULIC-LLVKDONJSA-N 0.000 description 1
- WFAZKGCKGCUHAN-GFCCVEGCSA-N (5r)-3-[3-fluoro-4-[6-(1-methyltetrazol-5-yl)pyridin-3-yl]phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one Chemical compound CN1N=NN=C1C1=CC=C(C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)C=N1 WFAZKGCKGCUHAN-GFCCVEGCSA-N 0.000 description 1
- HZEVZXKDXWYDKO-UHFFFAOYSA-N 1,3-oxazolidin-2-one;phosphoric acid Chemical class OP(O)(O)=O.O=C1NCCO1 HZEVZXKDXWYDKO-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- 108010077805 Bacterial Proteins Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000004708 ribosome subunit Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960003879 tedizolid Drugs 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
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- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
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- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- 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
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- 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
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- Animal Behavior & Ethology (AREA)
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Abstract
The invention discloses a preparation method of tedizolid phosphate for injection, which comprises the following steps: step A: preparing tedizolid phosphate, a freeze-drying protective agent, an alkaline pH regulator and an acidic pH regulator from raw materials; and B: preparing a mixed pharmaceutical preparation, adding tedizolid phosphate and a freeze-drying protective agent into water for injection, and adjusting the pH to 7.7-7.9 by using an alkaline pH regulator and an acidic pH regulator; the alkaline pH regulator adopts a sodium hydroxide solution with the concentration of 2M-4M; the lyoprotectant adopts a mixture of mannitol and sucrose. The tedizolid phosphate for injection prepared by the method has stable components and higher purity.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to tedizolid phosphate for injection and a preparation method thereof.
Background
Tedizolid Phosphate (Tedizolid Phosphate) is a novel oxazolidinone precursor antibiotic and is rapidly converted into a microbiologically active group, Tedizolid under the action of phosphatase in vivo. Tedizolids inhibit bacterial protein synthesis by binding to the Peptidyl Transferase Center (PTC) of the bacterial 50S ribosomal subunit, and have in vitro and in vivo activity against gram-positive bacteria, including Staphylococcus aureus, Streptococcus and enterococcus faecalis. The tedizolid phosphate is used as an effective component of the tedizolid phosphate for injection, the performance of the tedizolid phosphate is relatively stable, and the research and development of the quality control of the tedizolid phosphate for injection are mostly concentrated in the preparation process, such as the selection of auxiliary materials, the control of process parameters and the like, so as to reduce the impurity content of the product and ensure the stable and qualified product quality.
Disclosure of Invention
Based on the technical background, the invention provides the tedizolid phosphate for injection and the preparation method thereof, which solve the problems, are beneficial to reducing the impurity content of the product and improving the stability of the product.
The invention is realized by the following technical scheme:
a preparation method of tedizolid phosphate for injection comprises the following steps:
step A: raw material preparation
Preparing tedizolid phosphate, a freeze-drying protective agent, an alkaline pH regulator and an acidic pH regulator;
and B: preparation of Mixed pharmaceutical formulations
Adding tedizolid phosphate and a freeze-drying protective agent into water for injection, and adjusting the pH to 7.7-7.9 by using an alkaline pH regulator and an acidic pH regulator;
the alkaline pH regulator adopts a sodium hydroxide solution with the concentration of 2M-4M; the lyoprotectant adopts a mixture of mannitol and sucrose.
Further preferably, the mass ratio of the mannitol to the sucrose is 6:1-15: 1.
Further preferably, the mass ratio of the mannitol to the sucrose is 8:1-10: 1.
Further preferably, the acid regulator is hydrochloric acid solution; more preferably, the concentration of the hydrochloric acid solution is 0.8M-2M.
Further preferably, the method further comprises a sterile filtration step and an aseptic filtration step after the preparation of the mixed pharmaceutical preparation.
Further preferably, the sterilizing filtration step: while stirring, the solution tank was pressurized with sterile nitrogen, and the mixed drug formulation was pressurized through a 0.22 μm sterilizing filter and transferred to a sterile stainless steel tank for temporary storage. The sterile filtration step: during the filling operation, the mixed pharmaceutical formulation is passed through a 0.22 μm sterilizing filter in an aseptic filling zone and into a buffer tank.
Further preferably, the step B specifically includes the steps of:
step B1: adding water for injection into the container;
step B2: gradually adding tedizolid phosphate into the container while stirring;
step B3: gradually adding sodium hydroxide solution into the mixing tank while stirring to reach the target pH value;
step B4: gradually adding mannitol into the mixing tank while stirring;
step B5: adding an alkaline pH regulator or an acidic pH regulator to regulate the pH value to a target pH value based on the pH requirement;
step B6: and (5) fixing the volume.
Further preferably, in the step B1, after the water for injection is added into the container, the container is cooled to 15.0-25.0 ℃.
The tedizolid phosphate for injection is prepared by the preparation method of the tedizolid phosphate for injection.
The invention has the following advantages and beneficial effects:
the invention improves the freeze-drying protective agent, takes mannitol as the main freeze-drying protective agent and takes cane sugar as the auxiliary material to play a reinforcing role; the method optimizes the pH value and the concentration of the alkaline pH regulator, and finally has the effects of reducing the water residue of the product, reducing the impurity content of the product and improving the stability of the product by strictly controlling the pH value and properly increasing the concentration of sodium hydroxide.
Drawings
The accompanying drawings, which are included to provide a further understanding of the embodiments of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the principles of the invention. In the drawings:
FIG. 1 is a flow chart illustrating the preparation of an embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples and accompanying drawings, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not meant to limit the present invention.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to one of ordinary skill in the art that: it is not necessary to employ these specific details to practice the present invention. In other instances, well-known structures, circuits, materials, or methods have not been described in detail so as not to obscure the present invention.
Example 1
The embodiment provides a preparation method of tedizolid phosphate for injection, which comprises the following specific steps:
step 1: ingredients
Weighing tedizolid phosphate (210mg) and a freeze-drying protective agent (95.5 mg of mannitol and 9.5mg of sucrose) according to the prescription amount; sodium hydroxide and hydrochloric acid were weighed.
Step 2: preparation of pH regulators
An appropriate amount of 2.5M NaOH and 1.0M HCl solution was prepared using water for injection (WFI) and cooled to 20 ℃.
And step 3: mixing pharmaceutical preparation solutions
Step 31: adding a proper amount of water for injection into the mixing tank, and cooling to 20 ℃.
Step 32: while stirring, the weighed tedizolid phosphate was gradually added to the mixing tank.
Step 33: while stirring, gradually adding NaOH solution into the mixing tank to reach the target pH value of 7.7-7.9.
Step 34: the solution samples were taken for interim testing at pH 7.7-7.9. While stirring, the weighed mixture of mannitol and sucrose was gradually added to the mixing tank.
Step 35: visual inspection of the degree of dissolution was performed and the solution sample was withdrawn for in-process testing: the pH value is 7.7-7.9.
Step 36: if necessary, adding a proper amount of NaOH solution or HCl solution, and adjusting the pH value to 7.7-7.9.
Step 37: solution samples were drawn for intermediate process testing: the pH value is 7.7-7.9.
Step 38: if necessary, water for injection is added, and the mixture is cooled to 20 ℃ to make the solution reach the final standard weight.
Solution samples were drawn for intermediate process testing: appearance, pH value and biological load, and meets the requirement of normal production.
And 4, step 4: sterilizing filtration
While stirring, the solution tank was pressurized with sterile nitrogen and the solution was transferred to a sterile stainless steel tank by pressurizing through a 0.22 μm sterilizing filter. Under the condition of room temperature (15.0-25.0 ℃), the temporary storage time of the solution is not more than 24 hours.
The filter is integrity checked before and after filtration.
And 5: sterile filtration
Samples were taken for bioburden examination prior to sterile filtration.
During the filling operation, the solution is passed successively through two 0.22 μm sterilizing filters (or equivalent grade) into a buffer tank in an aseptic filling zone, as required.
Step 6: packing material treatment
The polyethylene-tetrafluoroethylene membrane-coated brominated butyl rubber plug for freeze drying of 20mm injection is cleaned, sterilized and dried by adopting a verification procedure, and the sterile and dried plug is taken out from a sterile area.
And 7: aseptic filling, partial corking and loading
The solution was filled into vials to a target loading of 2.10ml using a filling apparatus and the partially stoppered vials were loaded into a freeze dryer.
And 8: freeze-drying
After loading the lyophilizer, the door was closed and sealed and after checking the lyophilizer program, the lyophilization cycle was started.
And step 9: rolling cover
The stoppered vials are transferred to a capper for capping. And the rolled medicine is subjected to visual inspection and sampling inspection.
Example 2
The embodiment provides a preparation method of tedizolid phosphate for injection, which comprises the following specific steps:
step 1: ingredients
Weighing tedizolid phosphate (210mg) and a freeze-drying protective agent (95.5 mg of mannitol and 9.5mg of sucrose) according to the prescription amount; sodium hydroxide and hydrochloric acid were weighed.
Step 2: preparation of pH regulators
An appropriate amount of 4.0M NaOH and 1.0M HCl solution was prepared using water for injection (WFI) and cooled to 20 ℃.
And step 3: mixing pharmaceutical preparation solutions
Step 31: adding a proper amount of water for injection into the mixing tank, and cooling to 20 ℃.
Step 32: while stirring, the weighed tedizolid phosphate was gradually added to the mixing tank.
Step 33: while stirring, gradually adding NaOH solution into the mixing tank to reach the target pH value of 7.7-7.9.
Step 34: the solution samples were taken for interim testing at pH 7.7-7.9. While stirring, the weighed mixture of mannitol and sucrose was gradually added to the mixing tank.
Step 35: visual inspection of the degree of dissolution was performed and the solution sample was withdrawn for in-process testing: the pH value is 7.7-7.9.
Step 36: if necessary, adding a proper amount of NaOH solution or HCl solution, and adjusting the pH value to 7.7-7.9.
Step 37: solution samples were drawn for intermediate process testing: the pH value is 7.7-7.9.
Step 38: if necessary, water for injection is added, and the mixture is cooled to 20 ℃ to make the solution reach the final standard weight.
Solution samples were drawn for intermediate process testing: appearance, pH value and biological load, and meets the requirement of normal production.
And 4, step 4: sterilizing filtration
While stirring, the solution tank was pressurized with sterile nitrogen and the solution was transferred to a sterile stainless steel tank by pressurizing through a 0.22 μm sterilizing filter. Under the condition of room temperature (15.0-25.0 ℃), the temporary storage time of the solution is not more than 24 hours.
The filter is integrity checked before and after filtration.
And 5: sterile filtration
Samples were taken for bioburden examination prior to sterile filtration.
During the filling operation, the solution is passed successively through two 0.22 μm sterilizing filters (or equivalent grade) into a buffer tank in an aseptic filling zone, as required.
Step 6: packing material treatment
The polyethylene-tetrafluoroethylene membrane-coated brominated butyl rubber plug for freeze drying of 20mm injection is cleaned, sterilized and dried by adopting a verification procedure, and the sterile and dried plug is taken out from a sterile area.
And 7: aseptic filling, partial corking and loading
The solution was filled into vials to a target loading of 2.10ml using a filling apparatus and the partially stoppered vials were loaded into a freeze dryer.
And 8: freeze-drying
After loading the lyophilizer, the door was closed and sealed and after checking the lyophilizer program, the lyophilization cycle was started.
And step 9: rolling cover
The stoppered vials are transferred to a capper for capping. And the rolled medicine is subjected to visual inspection and sampling inspection.
Example 3
The embodiment provides a preparation method of tedizolid phosphate for injection, which comprises the following specific steps:
step 1: ingredients
Weighing tedizolid phosphate (210mg) and a freeze-drying protective agent (95.5 mg of mannitol and 9.5mg of sucrose) according to the prescription amount; sodium hydroxide and hydrochloric acid were weighed.
Step 2: preparation of pH regulators
An appropriate amount of 3.2M NaOH and 1.0M HCl solution was prepared using water for injection (WFI) and cooled to 20 ℃.
And step 3: mixing pharmaceutical preparation solutions
Step 31: adding a proper amount of water for injection into the mixing tank, and cooling to 20 ℃.
Step 32: while stirring, the weighed tedizolid phosphate was gradually added to the mixing tank.
Step 33: while stirring, gradually adding NaOH solution into the mixing tank to reach the target pH value of 7.7-7.9.
Step 34: the solution samples were taken for interim testing at pH 7.7-7.9. While stirring, the weighed mixture of mannitol and sucrose was gradually added to the mixing tank.
Step 35: visual inspection of the degree of dissolution was performed and the solution sample was withdrawn for in-process testing: the pH value is 7.7-7.9.
Step 36: if necessary, adding a proper amount of NaOH solution or HCl solution, and adjusting the pH value to 7.7-7.9.
Step 37: solution samples were drawn for intermediate process testing: the pH value is 7.7-7.9.
Step 38: if necessary, water for injection is added, and the mixture is cooled to 20 ℃ to make the solution reach the final standard weight.
Solution samples were drawn for intermediate process testing: appearance, pH value and biological load, and meets the requirement of normal production.
And 4, step 4: sterilizing filtration
While stirring, the solution tank was pressurized with sterile nitrogen and the solution was transferred to a sterile stainless steel tank by pressurizing through a 0.22 μm sterilizing filter. Under the condition of room temperature (15.0-25.0 ℃), the temporary storage time of the solution is not more than 24 hours.
The filter is integrity checked before and after filtration.
And 5: sterile filtration
Samples were taken for bioburden examination prior to sterile filtration.
During the filling operation, the solution is passed successively through two 0.22 μm sterilizing filters (or equivalent grade) into a buffer tank in an aseptic filling zone, as required.
Step 6: packing material treatment
The polyethylene-tetrafluoroethylene membrane-coated brominated butyl rubber plug for freeze drying of 20mm injection is cleaned, sterilized and dried by adopting a verification procedure, and the sterile and dried plug is taken out from a sterile area.
And 7: aseptic filling, partial corking and loading
The solution was filled into vials to a target loading of 2.10ml using a filling apparatus and the partially stoppered vials were loaded into a freeze dryer.
And 8: freeze-drying
After loading the lyophilizer, the door was closed and sealed and after checking the lyophilizer program, the lyophilization cycle was started.
And step 9: rolling cover
The stoppered vials are transferred to a capper for capping. And the rolled medicine is subjected to visual inspection and sampling inspection.
Example 4
The embodiment provides a preparation method of tedizolid phosphate for injection, which comprises the following specific steps:
step 1: ingredients
Weighing tedizolid phosphate (210mg) and a freeze-drying protective agent (93.3 mg of mannitol and 11.7mg of sucrose) according to the prescription amount; sodium hydroxide and hydrochloric acid were weighed.
Step 2: preparation of pH regulators
An appropriate amount of 3.2M NaOH and 1.0M HCl solution was prepared using water for injection (WFI) and cooled to 20 ℃.
And step 3: mixing pharmaceutical preparation solutions
Step 31: adding a proper amount of water for injection into the mixing tank, and cooling to 20 ℃.
Step 32: while stirring, the weighed tedizolid phosphate was gradually added to the mixing tank.
Step 33: while stirring, gradually adding NaOH solution into the mixing tank to reach the target pH value of 7.7-7.9.
Step 34: the solution samples were taken for interim testing at pH 7.7-7.9. While stirring, the weighed mixture of mannitol and sucrose was gradually added to the mixing tank.
Step 35: visual inspection of the degree of dissolution was performed and the solution sample was withdrawn for in-process testing: the pH value is 7.7-7.9.
Step 36: if necessary, adding a proper amount of NaOH solution or HCl solution, and adjusting the pH value to 7.7-7.9.
Step 37: solution samples were drawn for intermediate process testing: the pH value is 7.7-7.9.
Step 38: if necessary, water for injection is added, and the mixture is cooled to 20 ℃ to make the solution reach the final standard weight.
Solution samples were drawn for intermediate process testing: appearance, pH value and biological load, and meets the requirement of normal production.
And 4, step 4: sterilizing filtration
While stirring, the solution tank was pressurized with sterile nitrogen and the solution was transferred to a sterile stainless steel tank by pressurizing through a 0.22 μm sterilizing filter. Under the condition of room temperature (15.0-25.0 ℃), the temporary storage time of the solution is not more than 24 hours.
The filter is integrity checked before and after filtration.
And 5: sterile filtration
Samples were taken for bioburden examination prior to sterile filtration.
During the filling operation, the solution is passed successively through two 0.22 μm sterilizing filters (or equivalent grade) into a buffer tank in an aseptic filling zone, as required.
Step 6: packing material treatment
The polyethylene-tetrafluoroethylene membrane-coated brominated butyl rubber plug for freeze drying of 20mm injection is cleaned, sterilized and dried by adopting a verification procedure, and the sterile and dried plug is taken out from a sterile area.
And 7: aseptic filling, partial corking and loading
The solution was filled into vials to a target loading of 2.10ml using a filling apparatus and the partially stoppered vials were loaded into a freeze dryer.
And 8: freeze-drying
After loading the lyophilizer, the door was closed and sealed and after checking the lyophilizer program, the lyophilization cycle was started.
And step 9: rolling cover
The stoppered vials are transferred to a capper for capping. And the rolled medicine is subjected to visual inspection and sampling inspection.
Example 5
The embodiment provides a preparation method of tedizolid phosphate for injection, which comprises the following specific steps:
step 1: ingredients
Weighing tedizolid phosphate (210mg) and a freeze-drying protective agent (97.5 mg of mannitol and 7.5mg of sucrose) according to the prescription amount; sodium hydroxide and hydrochloric acid were weighed.
Step 2: preparation of pH regulators
An appropriate amount of 3.2M NaOH and 1.0M HCl solution was prepared using water for injection (WFI) and cooled to 20 ℃.
And step 3: mixing pharmaceutical preparation solutions
Step 31: adding a proper amount of water for injection into the mixing tank, and cooling to 20 ℃.
Step 32: while stirring, the weighed tedizolid phosphate was gradually added to the mixing tank.
Step 33: while stirring, gradually adding NaOH solution into the mixing tank to reach the target pH value of 7.7-7.9.
Step 34: the solution samples were taken for interim testing at pH 7.7-7.9. While stirring, the weighed mixture of mannitol and sucrose was gradually added to the mixing tank.
Step 35: visual inspection of the degree of dissolution was performed and the solution sample was withdrawn for in-process testing: the pH value is 7.7-7.9.
Step 36: if necessary, adding a proper amount of NaOH solution or HCl solution, and adjusting the pH value to 7.7-7.9.
Step 37: solution samples were drawn for intermediate process testing: the pH value is 7.7-7.9.
Step 38: if necessary, water for injection is added, and the mixture is cooled to 20 ℃ to make the solution reach the final standard weight.
Solution samples were drawn for intermediate process testing: appearance, pH value and biological load, and meets the requirement of normal production.
And 4, step 4: sterilizing filtration
While stirring, the solution tank was pressurized with sterile nitrogen and the solution was transferred to a sterile stainless steel tank by pressurizing through a 0.22 μm sterilizing filter. Under the condition of room temperature (15.0-25.0 ℃), the temporary storage time of the solution is not more than 24 hours.
The filter is integrity checked before and after filtration.
And 5: sterile filtration
Samples were taken for bioburden examination prior to sterile filtration.
During the filling operation, the solution is passed successively through two 0.22 μm sterilizing filters (or equivalent grade) into a buffer tank in an aseptic filling zone, as required.
Step 6: packing material treatment
The polyethylene-tetrafluoroethylene membrane-coated brominated butyl rubber plug for freeze drying of 20mm injection is cleaned, sterilized and dried by adopting a verification procedure, and the sterile and dried plug is taken out from a sterile area.
And 7: aseptic filling, partial corking and loading
The solution was filled into vials to a target loading of 2.10ml using a filling apparatus and the partially stoppered vials were loaded into a freeze dryer.
And 8: freeze-drying
After loading the lyophilizer, the door was closed and sealed and after checking the lyophilizer program, the lyophilization cycle was started.
And step 9: rolling cover
The stoppered vials are transferred to a capper for capping. And the rolled medicine is subjected to visual inspection and sampling inspection.
Comparative example 1
This comparative example provides a method for preparing tedizolid phosphate for injection, which comprises the following steps: the concentration of the NaOH solution was 0.7M.
Comparative example 2
This comparative example provides a method for preparing tedizolid phosphate for injection, which comprises the following steps: the concentration of the NaOH solution was 6M.
Comparative example 3
This comparative example provides a method for preparing tedizolid phosphate for injection, which comprises the following steps: the lyoprotectant adopts a mixture of 65mg of mannitol and 40mg of sucrose.
Comparative example 4
This comparative example provides a method for preparing tedizolid phosphate for injection, which comprises the following steps: the lyoprotectant adopts a mixture of 102mg of mannitol and 3mg of sucrose.
Comparative example 5
This comparative example provides a method for preparing tedizolid phosphate for injection, which comprises the following steps: the pH during the preparation process is 7.3.
Measurement of related substances and contents
The related substance types are: (R) -3- (4- (2- (2-methyltetrazol-5-yl) pyridin-5-yl) -3-fluorophenyl) -5-chlorooxazolidin-2-one, propyl 3- (4- (2- (2-methyltetrazol-5-yl) pyridin-5-yl) -3-fluoroanilino) -2-hydroxyphosphate, N- (2, 3-dihydroxypropyl) -4- (2- (2-methyltetrazol-5-yl) pyridin-5-yl) -3-fluoroaniline, and (R) -3- (4- (2- (2-methyltetrazol-5-yl) pyridin-5-yl) -3-fluorophenyl) -5-hydroxymethyloxa-nyl Oxazolidin-2-one dihydrogen phosphate dimer, (R) -3- (4- (2- (2-methyltetrazol-5-yl) pyridin-5-yl) -2-fluorophenyl) -5-hydroxymethyl oxazolidin-2-one, (R) -3- (4- (2- (1-methyltetrazol-5-yl) pyridin-5-yl) -3-fluorophenyl) -5-hydroxymethyl oxazolidin-2-one, (R) -3- (4- (2- (tetrazol-5-yl) pyridin-5-yl) -3-fluorophenyl) -5-hydroxymethyl oxazolidin-2-one, (R) -3- (4- (2- (2-methyltetrazol-5-yl) pyridin-5-yl) -3-fluorophenyl) -5-hydroxymethyloxazolidin-2-one.
Determination of related substances and C by high performance liquid chromatography17H18FN6O7The content of P.
Secondly, stability tests were conducted on the samples prepared in examples 1 to 5 and the samples prepared in control examples 1 to 5
1. High temperature stability test
The sample was placed in a 60 ℃ incubator for 20 days, and sampled at 0, 10 and 20 days, and the clarity, the content of the relevant substance and the content of the relevant substance were measured, respectively, and the measurement results are shown in Table 1.
TABLE 1 high temperature stability test results
2. High humidity stability test
The sample was placed in an incubator at a relative humidity of 90. + -. 5% for 20 days, and sampled at 0, 10 and 20 days, and then subjected to the clarity measurement, the measurement of the relevant substance and the content measurement, respectively, and the measurement results are shown in Table 2.
Table 2 high humidity stability test results
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A preparation method of tedizolid phosphate for injection is characterized by comprising the following steps:
step A: raw material preparation
Preparing tedizolid phosphate, a freeze-drying protective agent, an alkaline pH regulator and an acidic pH regulator;
and B: preparation of Mixed pharmaceutical formulations
Adding tedizolid phosphate and a freeze-drying protective agent into water for injection, and adjusting the pH to 7.7-7.9 by using an alkaline pH regulator and an acidic pH regulator;
the alkaline pH regulator adopts a sodium hydroxide solution with the concentration of 2M-4M;
the lyoprotectant adopts a mixture of mannitol and sucrose.
2. The preparation method of tedizolid phosphate for injection according to claim 1, wherein the mass ratio of the mannitol to the sucrose is 6:1-15: 1.
3. The preparation method of tedizolid phosphate for injection according to claim 2, wherein the mass ratio of mannitol to sucrose is 8:1-10: 1.
4. The method for preparing tedizolid phosphate for injection according to claim 1, wherein the acid regulator is hydrochloric acid solution.
5. The method for preparing tedizolid phosphate for injection according to claim 4, wherein the concentration of the hydrochloric acid solution is 0.8M-2M.
6. The method for preparing tedizolid phosphate for injection according to claim 1, further comprising a sterile filtration step and an aseptic filtration step after the preparation of the mixed pharmaceutical preparation.
7. The preparation method of tedizolid phosphate for injection according to claim 1,
the degerming and filtering step comprises the following steps: pressurizing the solution tank with sterile nitrogen while stirring, pressurizing the mixed medicinal preparation through a 0.22 μm sterilizing filter, and transferring to a sterile stainless steel tank for temporary storage;
the sterile filtration step: during the filling operation, the mixed pharmaceutical formulation is passed through a 0.22 μm sterilizing filter in an aseptic filling zone and into a buffer tank.
8. The preparation method of tedizolid phosphate for injection according to any one of claims 1 to 7, wherein the step B specifically comprises the following steps:
step B1: adding water for injection into the container;
step B2: gradually adding tedizolid phosphate into the container while stirring;
step B3: gradually adding sodium hydroxide solution into the mixing tank while stirring to reach the target pH value;
step B4: gradually adding mannitol into the mixing tank while stirring;
step B5: adding an alkaline pH regulator or an acidic pH regulator to regulate the pH value to a target pH value based on the pH requirement;
step B6: and (5) fixing the volume.
9. The method for preparing tedizolid phosphate for injection according to claim 8, wherein in the step B1, after the water for injection is added into the container, the temperature is cooled to 15.0-25.0 ℃.
10. Tedizolid phosphate for injection, which is prepared by the preparation method of the tedizolid phosphate for injection according to any one of claims 1 to 9.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105287407A (en) * | 2015-11-24 | 2016-02-03 | 南京正大天晴制药有限公司 | Tedizolid phosphate for injection |
| CN106344525A (en) * | 2016-11-08 | 2017-01-25 | 天津红日药业股份有限公司 | Tedizolid phosphate freeze-dried powder injection |
| CN107375220A (en) * | 2017-07-21 | 2017-11-24 | 苏州信恩医药科技有限公司 | A kind of Tedizolid Phosphate freeze drying powder injection and preparation method thereof |
| CN112826801A (en) * | 2021-01-08 | 2021-05-25 | 石家庄四药有限公司 | Preparation method of tedizolid phosphate freeze-dried preparation for injection |
| CN112957332A (en) * | 2021-02-04 | 2021-06-15 | 海南通用康力制药有限公司 | Tedizolid phosphate for injection and quality standard thereof |
| CN112957333A (en) * | 2021-02-05 | 2021-06-15 | 海南通用康力制药有限公司 | Tedizolid phosphate for injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105287407A (en) * | 2015-11-24 | 2016-02-03 | 南京正大天晴制药有限公司 | Tedizolid phosphate for injection |
| CN106344525A (en) * | 2016-11-08 | 2017-01-25 | 天津红日药业股份有限公司 | Tedizolid phosphate freeze-dried powder injection |
| CN107375220A (en) * | 2017-07-21 | 2017-11-24 | 苏州信恩医药科技有限公司 | A kind of Tedizolid Phosphate freeze drying powder injection and preparation method thereof |
| CN112826801A (en) * | 2021-01-08 | 2021-05-25 | 石家庄四药有限公司 | Preparation method of tedizolid phosphate freeze-dried preparation for injection |
| CN112957332A (en) * | 2021-02-04 | 2021-06-15 | 海南通用康力制药有限公司 | Tedizolid phosphate for injection and quality standard thereof |
| CN112957333A (en) * | 2021-02-05 | 2021-06-15 | 海南通用康力制药有限公司 | Tedizolid phosphate for injection and preparation method thereof |
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