CN111920781A - Preparation method of tedizolid phosphate preparation for injection - Google Patents
Preparation method of tedizolid phosphate preparation for injection Download PDFInfo
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- CN111920781A CN111920781A CN202010857514.4A CN202010857514A CN111920781A CN 111920781 A CN111920781 A CN 111920781A CN 202010857514 A CN202010857514 A CN 202010857514A CN 111920781 A CN111920781 A CN 111920781A
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- Prior art keywords
- tedizolid phosphate
- preparation
- tedizolid
- disodium
- injection
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- 229960003947 tedizolid phosphate Drugs 0.000 title claims abstract description 135
- 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 135
- 238000002360 preparation method Methods 0.000 title claims abstract description 95
- 238000002347 injection Methods 0.000 title claims abstract description 72
- 239000007924 injection Substances 0.000 title claims abstract description 72
- 229960003879 tedizolid Drugs 0.000 claims abstract description 36
- 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 claims abstract description 36
- 239000000463 material Substances 0.000 claims abstract description 22
- 239000002245 particle Substances 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims description 77
- 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 description 46
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 46
- 229930195725 Mannitol Natural products 0.000 claims description 46
- 239000000594 mannitol Substances 0.000 claims description 46
- 235000010355 mannitol Nutrition 0.000 claims description 46
- 238000009835 boiling Methods 0.000 claims description 39
- 238000005507 spraying Methods 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 16
- 238000005469 granulation Methods 0.000 claims description 8
- 230000003179 granulation Effects 0.000 claims description 8
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 7
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 7
- 239000008101 lactose Substances 0.000 claims description 7
- 229960003194 meglumine Drugs 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
- 238000009817 primary granulation Methods 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000008187 granular material Substances 0.000 description 25
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 7
- 238000011049 filling Methods 0.000 description 7
- 238000001514 detection method Methods 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 241000194022 Streptococcus sp. Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
Classifications
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- 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
- 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
- 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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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation method of a tedizolid phosphate preparation for injection. The preparation method of the tedizolid phosphate disodium preparation for injection comprises the steps of granulating the tedizolid phosphate disodium salt, and then wrapping the tedizolid phosphate disodium salt particles with water-soluble auxiliary materials to obtain the tedizolid phosphate disodium preparation for injection; the mass ratio of the water-soluble auxiliary material to the tedizolid phosphate is 1:0.2-10 based on the mass of the tedizolid contained in the tedizolid phosphate disodium salt. The preparation method of the tedizolid phosphate preparation for injection has low production cost and high production efficiency, can prepare the tedizolid phosphate disodium salt which is extremely easy to absorb moisture and has extremely poor liquidity into the tedizolid phosphate preparation which is difficult to absorb moisture and has good liquidity, and is easy to carry out sterile subpackage.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation method of a tedizolid phosphate preparation for injection.
Background
Tedizolid phosphate for injection belongs to oxazolidinone antibacterial drugs, and is used for treating acute bacterial skin and skin tissue infection (ABSSSI) caused by the following gram-positive bacteria sensitive strains: staphylococcus aureus (including methicillin-resistant [ MRSA ] and methicillin-sensitive [ MSSA ] strains), streptococcus pyogenes, streptococcus agalactiae, streptococcus sp.
The active ingredient of the tedizolid phosphate for injection is the tedizolid phosphate, wherein the tedizolid phosphate is difficult to dissolve in water and cannot be prepared into injection, and needs to react with sodium hydroxide to produce disodium salt which is easy to dissolve in water, but the disodium salt of the tedizolid phosphate is extremely easy to absorb moisture and has poor liquidity, and aseptic subpackaging cannot be carried out.
The tedizolid phosphate for injection on the market at present is basically freeze-dried, the production cycle of freeze-drying is long, one production cycle is about two days or more, the capacity is limited by a freeze dryer, and the production quantity of each batch is small.
Disclosure of Invention
The invention aims to provide a preparation method of a tedizolid phosphate preparation for injection, which has low production cost and high production efficiency, can prepare a tedizolid phosphate disodium salt which is extremely easy to absorb moisture and has extremely poor liquidity into a tedizolid phosphate preparation which is difficult to absorb moisture and has good liquidity, and is easy to carry out sterile subpackage.
The preparation method of the tedizolid phosphate disodium preparation for injection comprises the steps of granulating the tedizolid phosphate disodium salt, and then wrapping the tedizolid phosphate disodium salt particles with water-soluble auxiliary materials to obtain the tedizolid phosphate disodium preparation for injection;
the water content of the disodium tedizolid phosphate before granulation is 3 to 40 weight percent, preferably 5 to 30 weight percent, and more preferably 10 to 25 weight percent.
The preparation method of the tedizolid phosphate preparation for injection comprises the following specific steps: carrying out primary granulation on the tedizolid phosphate by adopting a boiling drying granulator, then spraying and drying the water solution containing the water-soluble auxiliary materials to enable the water-soluble auxiliary materials to wrap the tedizolid phosphate, and carrying out sterile subpackaging to obtain the tedizolid phosphate preparation for injection.
The water-soluble adjuvant is one of mannitol, lactose, meglumine and arginine; preferably mannitol or lactose; mannitol is more preferable.
The water-soluble auxiliary material accounts for 0.5-50 wt% of the water solution containing the water-soluble auxiliary material, preferably 5-40 wt%, more preferably 10-35 wt%, and most preferably 15-30 wt%.
The mass ratio of the water-soluble auxiliary material to the tedizolid phosphate is 1:0.2-10, preferably 1:0.5-5, and more preferably 1:1-5, based on the mass of the tedizolid contained in the tedizolid phosphate disodium salt.
The water-soluble auxiliary materials are less, so that the auxiliary materials can not completely wrap the tedizolid phosphate, and the tedizolid phosphate still easily absorbs moisture; the osmotic pressure during administration is affected when the amount of the water-soluble auxiliary material is a certain amount.
The primary granulation adopts normal temperature fluidized granulation, the granulation atmosphere is sterile air, and the granulation time is 5-15 min.
After the water solution containing water-soluble auxiliary materials is sprayed, the water content is controlled to be 0.5-2.5 wt%.
Preferably, the preparation method of the disodium tedizolid phosphate preparation for injection comprises the following specific steps:
(1) adding tedizolid phosphate with the water content of 10-25 wt% into a boiling drying granulator, introducing sterile air into the boiling drying granulator, and granulating for 5-15min at normal temperature;
(2) setting the air inlet temperature of a boiling drying granulator to be 55-80 ℃, spraying a mannitol aqueous solution with the concentration of 15-30 wt% after degerming and filtering, and drying and granulating; when the total mass of the sprayed mannitol is 20-100% of the mass of the tedizolid phosphate (calculated by the tedizolid), stopping spraying, continuing drying for a certain time, stopping drying, and controlling the water content to be 0.5-2.5 wt%;
(3) and (3) carrying out sterile subpackage on the prepared granules, and subpackaging the granules with the specification (calculated by tedizolid) of 0.2g to obtain the disodium tedizolid phosphate preparation for injection.
Compared with the prior art, the invention has the following beneficial effects:
(1) according to the invention, by utilizing the characteristics of good solubility and weak hygroscopicity of water-soluble auxiliary materials, especially mannitol, the raw materials containing certain moisture are made into granules by a boiling drying granulator, then the mannitol is sprayed on the surfaces of the granules, and the moisture-proof effect can be achieved after the mannitol is coated;
(2) the powdery disodium tedizolid phosphate is prepared into granules, so that the surface area is greatly reduced, the hygroscopicity is reduced, and the fluidity of the disodium tedizolid phosphate preparation is improved;
(3) the preparation method has low production cost and high production efficiency, can prepare the tedizolid phosphate disodium salt which is extremely easy to absorb moisture and has extremely poor liquidity into the tedizolid phosphate disodium salt preparation which is difficult to absorb moisture and has good liquidity, and is easy to carry out sterile subpackage.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
A tedizolid phosphate preparation for injection is prepared from the following components in parts by weight:
tedizolid phosphate disodium salt (calculated as tedizolid): 10 kg;
mannitol: 5 kg.
The preparation process comprises the following steps:
(1) adding tedizolid phosphate with the water content of 10 wt% into a boiling drying granulator, introducing sterile air into the boiling drying granulator, and granulating for 10min at normal temperature;
(2) setting the air inlet temperature of a boiling drying granulator to 70 ℃, spraying a 20 wt% mannitol aqueous solution after degerming and filtering, and drying and granulating; when the total mass of the sprayed mannitol is 50% of the mass of the tedizolid phosphate (calculated by the tedizolid), stopping spraying, and continuing drying for 10min and stopping drying;
(3) and (3) carrying out sterile subpackage on the prepared granules, and subpackaging the granules with the specification (calculated by tedizolid) of 0.2g to obtain the disodium tedizolid phosphate preparation for injection.
The results are shown in table 1:
table 1 test results of the disodium tedizolid phosphate preparation for injection prepared in example 1
And (4) conclusion:
the filling quantity difference shows that the prepared particles have better fluidity, and the prepared samples have better stability through an accelerated test.
Example 2
A tedizolid phosphate preparation for injection is prepared from the following components in parts by weight:
tedizolid phosphate disodium salt (calculated as tedizolid): 10 kg;
mannitol: 5 kg.
The preparation process comprises the following steps:
(1) adding tedizolid phosphate with the water content of 25 wt% into a boiling drying granulator, introducing sterile air into the boiling drying granulator, and granulating for 10min at normal temperature;
(2) setting the air inlet temperature of a boiling drying granulator to 70 ℃, spraying 40 wt% mannitol aqueous solution (heated for dissolution and filtered while hot) after degerming and filtering, and drying and granulating; when the total mass of the sprayed mannitol is 50% of the mass of the tedizolid phosphate (calculated by the tedizolid), stopping spraying, and continuing drying for 10min and stopping drying;
(3) and (3) carrying out sterile subpackage on the prepared granules, and subpackaging the granules with the specification (calculated by tedizolid) of 0.2g to obtain the disodium tedizolid phosphate preparation for injection.
The results are shown in table 2:
table 2 test results of the disodium tedizolid phosphate preparation for injection prepared in example 2
And (4) conclusion:
the filling quantity difference shows that the prepared particles have better fluidity, and the prepared samples have better stability through an accelerated test.
Example 3
A tedizolid phosphate preparation for injection is prepared from the following components in parts by weight:
tedizolid phosphate disodium salt (calculated as tedizolid): 10 kg;
mannitol: 4 kg.
The preparation process comprises the following steps:
(1) adding tedizolid phosphate with the water content of 20 wt% into a boiling drying granulator, introducing sterile air into the boiling drying granulator, and granulating for 10min at normal temperature;
(2) setting the air inlet temperature of a boiling drying granulator to 70 ℃, spraying a mannitol aqueous solution with the concentration of 15 wt% after degerming and filtering, and drying and granulating; when the total mass of the sprayed mannitol is 40% of the mass of the tedizolid phosphate (calculated by the tedizolid), stopping spraying, and continuing drying for 10min and stopping drying;
(3) and (3) carrying out sterile subpackage on the prepared granules, and subpackaging the granules with the specification (calculated by tedizolid) of 0.2g to obtain the disodium tedizolid phosphate preparation for injection.
The results are shown in table 3:
table 3 test results of the disodium tedizolid phosphate preparation for injection prepared in example 3
And (4) conclusion:
the filling quantity difference shows that the prepared particles have better fluidity, and the prepared samples have better stability through an accelerated test.
Example 4
A tedizolid phosphate preparation for injection is prepared from the following components in parts by weight:
tedizolid phosphate disodium salt (calculated as tedizolid): 10 kg;
mannitol: 6 kg.
The preparation process comprises the following steps:
(1) adding tedizolid phosphate with the water content of 15 wt% into a boiling drying granulator, introducing sterile air into the boiling drying granulator, and granulating for 10min at normal temperature;
(2) setting the air inlet temperature of a boiling drying granulator to 70 ℃, spraying a 20 wt% mannitol aqueous solution after degerming and filtering, and drying and granulating; when the total mass of the sprayed mannitol is 60 percent of the mass of the tedizolid phosphate (calculated by the tedizolid), stopping spraying, and continuing drying for 10min and stopping drying;
(3) and (3) carrying out sterile subpackage on the prepared granules, and subpackaging the granules with the specification (calculated by tedizolid) of 0.2g to obtain the disodium tedizolid phosphate preparation for injection.
The results are shown in table 4:
table 4 test results of the disodium tedizolid phosphate preparation for injection prepared in example 4
And (4) conclusion:
the filling quantity difference shows that the prepared particles have better fluidity, and the prepared samples have better stability through an accelerated test.
Example 5
A tedizolid phosphate preparation for injection is prepared from the following components in parts by weight:
tedizolid phosphate disodium salt (calculated as tedizolid): 10 kg;
mannitol: 5 kg.
The preparation process comprises the following steps:
(1) adding tedizolid phosphate with the water content of 15 wt% into a boiling drying granulator, introducing sterile air into the boiling drying granulator, and granulating for 10min at normal temperature;
(2) setting the air inlet temperature of a boiling drying granulator to 70 ℃, spraying a 20 wt% mannitol aqueous solution after degerming and filtering, and drying and granulating; when the total mass of the sprayed mannitol is 50% of the mass of the tedizolid phosphate (calculated by the tedizolid), stopping spraying, and continuing drying for 10min and stopping drying;
(3) and (3) carrying out sterile subpackage on the prepared granules, and subpackaging the granules with the specification (calculated by tedizolid) of 0.2g to obtain the disodium tedizolid phosphate preparation for injection.
The results are shown in table 5:
table 5 test results of the disodium tedizolid phosphate preparation for injection prepared in example 5
And (4) conclusion:
the filling quantity difference shows that the prepared particles have good fluidity, the quality of the prepared product is good as can be seen from the inspection data of 0 day, and the stability of the prepared sample is good as can be seen through an accelerated test.
As can be seen from examples 1-5, the disodium tedizolid phosphate preparation for injection prepared by the invention has controllable quality and good stability.
Example 6
A tedizolid phosphate preparation for injection is prepared from the following components in parts by weight:
tedizolid phosphate disodium salt (calculated as tedizolid): 10 kg;
mannitol: 2 kg.
The preparation process comprises the following steps:
(1) adding tedizolid phosphate with the water content of 15 wt% into a boiling drying granulator, introducing sterile air into the boiling drying granulator, and granulating for 10min at normal temperature;
(2) setting the air inlet temperature of a boiling drying granulator to 70 ℃, spraying a 20 wt% mannitol aqueous solution after degerming and filtering, and drying and granulating; when the total mass of the sprayed mannitol is 20 percent of the mass of the tedizolid phosphate (calculated by the tedizolid), stopping spraying, and continuing drying for 10min and stopping drying;
(3) and (3) carrying out sterile subpackage on the prepared granules, and subpackaging the granules with the specification (calculated by tedizolid) of 0.2g to obtain the disodium tedizolid phosphate preparation for injection.
The results are shown in Table 6:
table 6 test results of the disodium tedizolid phosphate preparation for injection prepared in example 6
And (4) conclusion:
as can be seen from the difference in the amount of mannitol, the difference in the amount of mannitol increases, the moisture of the prepared sample also increases, and the stability is deteriorated in the case of high moisture.
Example 7
A tedizolid phosphate preparation for injection is prepared from the following components in parts by weight:
tedizolid phosphate disodium salt (calculated as tedizolid): 10 kg;
mannitol: 10 kg.
The preparation process comprises the following steps:
(1) adding tedizolid phosphate with the water content of 15 wt% into a boiling drying granulator, introducing sterile air into the boiling drying granulator, and granulating for 10min at normal temperature;
(2) setting the air inlet temperature of a boiling drying granulator to 70 ℃, spraying a mannitol aqueous solution with the concentration of 30 wt% after degerming and filtering, and drying and granulating; when the total mass of the sprayed mannitol is 100 percent of the mass of the tedizolid phosphate (calculated by the tedizolid), stopping spraying, and continuing drying for 10min and stopping drying;
(3) and (3) carrying out sterile subpackage on the prepared granules, and subpackaging the granules with the specification (calculated by tedizolid) of 0.2g to obtain the disodium tedizolid phosphate preparation for injection.
The results are shown in Table 7:
table 7 test results of the disodium tedizolid phosphate preparation for injection prepared in example 7
And (4) conclusion:
as can be seen from the difference of the loading amount, the prepared sample has better fluidity, and the related substances are slightly larger than other formulas at 0 day, which is caused by longer time under the high-temperature and high-humidity condition in the preparation process.
Example 8
A tedizolid phosphate preparation for injection is prepared from the following components in parts by weight:
tedizolid phosphate disodium salt (calculated as tedizolid): 10 kg;
lactose: 5 kg.
The preparation process comprises the following steps:
(1) adding tedizolid phosphate with the water content of 15 wt% into a boiling drying granulator, introducing sterile air into the boiling drying granulator, and granulating for 10min at normal temperature;
(2) setting the air inlet temperature of a boiling drying granulator to 70 ℃, spraying the lactose aqueous solution with the concentration of 20 wt% after degerming and filtering, and drying and granulating; when the total mass of the sprayed lactose is 50% of the mass of the tedizolid phosphate (calculated by the tedizolid), stopping spraying, and continuing drying for 10min and stopping drying;
(3) and (3) carrying out sterile subpackage on the prepared granules, and subpackaging the granules with the specification (calculated by tedizolid) of 0.2g to obtain the disodium tedizolid phosphate preparation for injection.
The results are shown in Table 8:
table 8 test results of the disodium tedizolid phosphate preparation for injection prepared in example 8
And (4) conclusion:
the filling quantity difference shows that the prepared particles have good fluidity, the quality of the prepared product is good as can be seen from the inspection data of 0 day, and the stability of the prepared sample is good as can be seen through an accelerated test.
Example 9
A tedizolid phosphate preparation for injection is prepared from the following components in parts by weight:
tedizolid phosphate disodium salt (calculated as tedizolid): 10 kg;
meglumine: 5 kg.
The preparation process comprises the following steps:
(1) adding tedizolid phosphate with the water content of 15 wt% into a boiling drying granulator, introducing sterile air into the boiling drying granulator, and granulating for 10min at normal temperature;
(2) setting the air inlet temperature of a boiling drying granulator to 70 ℃, spraying a 20 wt% aqueous solution of meglumine after degerming and filtering, and drying and granulating; when the total mass of the sprayed meglumine is 50% of the mass of the tedizolid phosphate (calculated by the tedizolid), stopping spraying, and continuing drying for 10min and stopping drying;
(3) and (3) carrying out sterile subpackage on the prepared granules, and subpackaging the granules with the specification (calculated by tedizolid) of 0.2g to obtain the disodium tedizolid phosphate preparation for injection.
The results are shown in Table 9:
table 9 test results of the disodium tedizolid phosphate preparation for injection prepared in example 9
And (4) conclusion:
the filling quantity difference shows that the prepared particles have good fluidity, and the stability data shows that the fluidity and the moisture absorption problem during product subpackaging can be effectively solved by using the meglumine, but the stability of the product can be influenced to a certain extent due to the high alkalinity of the meglumine.
Comparative example 1
Meanwhile, compared with the difference in stability of the tedizolid phosphate for injection prepared by the freeze-drying method, the detection results of the tedizolid phosphate for injection prepared by the freeze-drying method are shown in table 10:
TABLE 10 detection results of disodium tedizolid phosphate preparation for injection prepared by freeze-drying method
Compared with the sample prepared by the method, the sample prepared by the freeze drying method increases related substances slightly quickly, and other detection preparations are equivalent to the method. The reason is that the sample prepared by freeze-drying is amorphous powder, so that the surface area of the product is large, and the stability of the product is poor.
Comparative example 2
The comparative example is added with a small amount of mannitol to prepare the tedizolid phosphate preparation for injection, and the formula is as follows:
tedizolid phosphate disodium salt (calculated as tedizolid): 10 kg;
mannitol: 0.7 kg.
The preparation process comprises the following steps:
(1) adding tedizolid phosphate with the water content of 10 wt% into a boiling drying granulator, introducing sterile air into the boiling drying granulator, and granulating for 10min at normal temperature;
(2) setting the air inlet temperature of a boiling drying granulator to 70 ℃, spraying a 20 wt% mannitol aqueous solution after degerming and filtering, and drying and granulating; continuing drying for 10min until the spraying is finished, and stopping drying;
(3) the prepared granules are subjected to aseptic subpackage, the subpackage specification (calculated by tedizolid) is 0.2g, and sampling detection is carried out on different subpackage time points.
The results are shown in Table 11:
TABLE 11 detection results of disodium tedizolid phosphate preparation for injection prepared in comparative example 2
The results show that the product has poor fluidity when the addition amount of the mannitol is low, and has serious moisture absorption phenomenon in the subpackaging process, and the subpackaging can not be carried out when the subpackaging lasts for 30 minutes; the reason is that the mannitol can lead to incomplete wrapping of the auxiliary materials on the raw materials when the mannitol is added in a low amount, and moisture absorption is generated in the subsequent subpackaging process, so that the stability in the later period is influenced, and the later-period subpackaging cannot be carried out.
Comparative example 3
The comparative example is added with a small amount of mannitol to prepare the tedizolid phosphate preparation for injection, and the formula is as follows:
tedizolid phosphate disodium salt (calculated as tedizolid): 3 kg;
mannitol: 18 kg.
The preparation process comprises the following steps:
(1) adding tedizolid phosphate with the water content of 10 wt% into a boiling drying granulator, introducing sterile air into the boiling drying granulator, and granulating for 10min at normal temperature;
(2) setting the air inlet temperature of a boiling drying granulator to 70 ℃, spraying a 20 wt% mannitol aqueous solution after degerming and filtering, drying and granulating until spraying is finished, and stopping drying after continuing drying for 10 min;
(3) the prepared granules are subjected to aseptic subpackage, the subpackage specification (calculated by tedizolid) is 0.2g, and sampling detection is carried out on different subpackage time points.
The results are shown in table 12:
table 12 test results of the disodium tedizolid phosphate preparation for injection prepared in comparative example 3
As can be seen from the results, the production time of the product is significantly prolonged when the mannitol is added in a high amount, and the related substances are significantly increased under the conditions of high temperature and high humidity for a long time. When the mannitol is added to wrap the raw materials, the significance of increasing the added amount is not large, the more the mannitol is added, the longer the production period is, the larger the loading amount during later-stage subpackaging is, and the osmotic pressure during administration can be influenced when the added amount reaches a certain degree.
Claims (9)
1. A preparation method of a tedizolid phosphate preparation for injection is characterized by comprising the following steps: granulating the tedizolid phosphate disodium salt, and then wrapping the tedizolid phosphate disodium salt particles with water-soluble auxiliary materials to obtain a tedizolid phosphate disodium salt preparation for injection;
the mass ratio of the water-soluble auxiliary material to the tedizolid phosphate is 1:0.2-10 based on the mass of the tedizolid contained in the tedizolid phosphate disodium salt.
2. The method for preparing a disodium tedizolid phosphate preparation for injection according to claim 1, wherein the disodium tedizolid phosphate preparation for injection comprises the following steps: carrying out primary granulation on the tedizolid phosphate by adopting a boiling drying granulator, then spraying and drying the water solution containing the water-soluble auxiliary materials to enable the water-soluble auxiliary materials to wrap the tedizolid phosphate, and carrying out sterile subpackaging to obtain the tedizolid phosphate preparation for injection.
3. The method for preparing the disodium tedizolid phosphate preparation for injection according to claim 1 or 2, wherein the disodium tedizolid phosphate preparation for injection comprises the following steps: the water content of the disodium tedizolid phosphate before granulation is 3-40 wt%.
4. The method for preparing the disodium tedizolid phosphate preparation for injection according to claim 1 or 2, wherein the disodium tedizolid phosphate preparation for injection comprises the following steps: the water-soluble adjuvant is one of mannitol, lactose, meglumine and arginine.
5. The method for preparing the disodium tedizolid phosphate preparation for injection according to claim 1 or 2, wherein the disodium tedizolid phosphate preparation for injection comprises the following steps: the water-soluble adjuvant is mannitol or lactose.
6. The method for preparing the disodium tedizolid phosphate preparation for injection according to claim 1 or 2, wherein the disodium tedizolid phosphate preparation for injection comprises the following steps: the water-soluble auxiliary material is mannitol.
7. The method for preparing a disodium tedizolid phosphate preparation for injection according to claim 2, wherein the disodium tedizolid phosphate preparation for injection comprises the following steps: the water-soluble auxiliary material accounts for 0.5-50 wt% in the water solution containing the water-soluble auxiliary material.
8. The method for preparing a disodium tedizolid phosphate preparation for injection according to claim 2, wherein the disodium tedizolid phosphate preparation for injection comprises the following steps: after the water solution containing water-soluble auxiliary materials is sprayed, the water content is controlled to be 0.5-2.5 wt%.
9. The method for preparing a disodium tedizolid phosphate preparation for injection according to claim 2, wherein the disodium tedizolid phosphate preparation for injection comprises the following steps: the primary granulation adopts normal temperature fluidized granulation, the granulation atmosphere is sterile air, and the granulation time is 5-15 min.
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