CN115590825B - Daptomycin for injection and preparation method thereof - Google Patents
Daptomycin for injection and preparation method thereof Download PDFInfo
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- CN115590825B CN115590825B CN202211291952.4A CN202211291952A CN115590825B CN 115590825 B CN115590825 B CN 115590825B CN 202211291952 A CN202211291952 A CN 202211291952A CN 115590825 B CN115590825 B CN 115590825B
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- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 239000007788 liquid Substances 0.000 claims abstract description 47
- 239000003814 drug Substances 0.000 claims abstract description 43
- 108010013198 Daptomycin Proteins 0.000 claims abstract description 36
- 229960005484 daptomycin Drugs 0.000 claims abstract description 36
- 238000004108 freeze drying Methods 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 238000011049 filling Methods 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 10
- 230000001276 controlling effect Effects 0.000 claims description 6
- 238000012792 lyophilization process Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000007599 discharging Methods 0.000 claims description 5
- 238000007710 freezing Methods 0.000 claims description 5
- 230000008014 freezing Effects 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 5
- 238000003825 pressing Methods 0.000 claims description 5
- 230000001105 regulatory effect Effects 0.000 claims description 5
- 230000001954 sterilising effect Effects 0.000 claims description 4
- 239000012535 impurity Substances 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 7
- 238000003860 storage Methods 0.000 abstract description 5
- 230000000052 comparative effect Effects 0.000 description 21
- 230000015556 catabolic process Effects 0.000 description 8
- 238000006731 degradation reaction Methods 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000012488 sample solution Substances 0.000 description 7
- 238000000859 sublimation Methods 0.000 description 7
- 230000008022 sublimation Effects 0.000 description 7
- 230000008569 process Effects 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 238000011056 performance test Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000000413 hydrolysate Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 206010003694 Atrophy Diseases 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 108010009736 Protein Hydrolysates Proteins 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 239000006012 monoammonium phosphate Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 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 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- 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
Abstract
The invention discloses daptomycin for injection and a preparation method thereof, and relates to the technical field of daptomycin preparation. The preparation method comprises the following steps: controlling the water temperature to be 2-8 ℃, adding a small amount of daptomycin in advance in a stirring state, and synchronously adding a pH regulator when the pH of the liquid medicine is reduced to 4.0 until the daptomycin is completely dissolved, wherein the total added weight of the daptomycin is 50-150 parts; adjusting the pH value of the end point of the liquid medicine to be maintained at 4.0-7.0, and adding water until the total weight is 1000 parts; filtering the liquid medicine, filling and freeze-drying to obtain pale yellow loose block. The method controls the pH value, the liquid preparation temperature, the pH regulator concentration, the daptomycin concentration and the like in the liquid medicine preparation process, solves the problems of stickiness and caking, low efficiency and the like in the liquid medicine preparation process, mainly degrades impurities without obvious increase in different storage time, has higher liquid medicine stability and less impurity content, and has good freeze-drying effect and short re-dissolving time.
Description
Technical Field
The invention relates to the technical field of daptomycin preparation, in particular to daptomycin for injection and a preparation method thereof.
Background
With the continuous emergence of new antibiotics, bacterial resistance to antibiotics is continuously upgraded, and daptomycin for injection is called as the last line of defense for drug-resistant antibiotics. Daptomycin acts on a mechanism different from any other antibiotic, daptomycin binds to the bacterial cell membrane and causes rapid depolarization of the cell membrane potential. This loss of cell membrane potential inhibits DNA, RNA and protein synthesis, ultimately leading to bacterial cell death. Due to the unique property, pathogenic bacteria can be killed rapidly, the probability of drug-resistant bacteria is greatly reduced, and the drug-resistant bacteria cannot be influenced by cross drug resistance caused by other antibiotics. Compared with the traditional antibiotic administration (at least 1 day and 2 times), the daptomycin for injection only needs to be administered 1 day and 1 time, so that the medical cost expenditure is effectively reduced, and patients which cannot tolerate other antibiotic treatment can be treated.
However, daptomycin has poor stability, many and complex impurities, light weight, moisture absorption, easy viscosity induction, low solubility in water, pH dependency, and easy foaming, stickiness and agglomeration and degradation after dissolution. Therefore, the raw materials have the problems of long dissolution time, poor freeze-drying effect, more impurities, poor stability and the like in the preparation process.
Disclosure of Invention
The invention provides daptomycin for injection and a preparation method thereof, which are used for solving the technical problems of long dissolution time, poor freeze-drying effect, more impurities and poor stability of a daptomycin preparation.
In order to solve the technical problems, one of the purposes of the invention is to provide a preparation method of daptomycin for injection, which comprises the following steps:
(1) Preparing part of water, and controlling the water temperature to be 2-8 ℃;
(2) Slowly adding a small amount of daptomycin in advance in a stirring state, and synchronously adding a pH regulator with the concentration of 0.1-3.0mol/L when the pH of the liquid medicine is reduced to 4.0, wherein the daptomycin is continuously added, and the pH value of the liquid medicine is synchronously regulated to be kept within the range of 4.0-7.0 until the daptomycin is completely dissolved, wherein the total added weight of the daptomycin is 50-150 parts;
(3) After the daptomycin is completely dissolved, regulating the end point pH value of the liquid medicine to be maintained at 4.0-7.0, and then adding water to 1000 parts of the total weight;
(4) Filtering the liquid medicine, filling, and freeze-drying in a freeze-drying device to obtain pale yellow loose block;
in step (4), the lyophilization process comprises the steps of:
s01, precooling: the temperature of the box entering is 0-5 ℃;
s02, pre-freezing: cooling to-30 to-45 ℃ and keeping for 2-4 hours;
s03, sublimating: starting a vacuum pump, vacuumizing to below 20Pa, heating to-5 ℃ to 0 ℃ at a constant speed of 15-20 ℃/h, and keeping for 10-15 hours:
s04, drying: heating to 20-25 ℃ at a constant speed of 20-25 ℃/h, and drying for 4-8 hours;
s05, after heat preservation is finished, vacuum plugging, re-pressing and discharging.
Preferably, in the step (1), the water for preparation is 20% -70% of the total volume.
Preferably, in the step (2), the pH adjuster is one or more of hydrochloric acid, lactic acid, acetic acid, phosphoric acid, disodium hydrogen phosphate, citric acid, sodium citrate, sodium bicarbonate and sodium hydroxide solution.
Preferably, the pH regulator is sodium hydroxide solution.
Preferably, in step (4), the medicinal solution is filtered through a two-stage 0.22 μm sterilization filter.
Preferably, in the step (2), the total added weight part of the daptomycin is 75-125 parts.
Preferably, in the step (3), the final pH value of the liquid medicine is adjusted to 4.0-5.0.
By adopting the scheme, the higher the pH value of the liquid medicine is, the faster the dissolution rate of daptomycin is, the shorter the preparation time is, but the main degradation impurities can also be increased along with the increase of the pH value, the end point pH value of the liquid medicine is limited to be 4.0-5.0, and the comprehensive consideration is given to controlling the acceptable range of the degradation rate of the impurities.
In order to solve the technical problems, the second object of the present invention is to provide daptomycin for injection, which is prepared by the preparation method of daptomycin for injection.
Compared with the prior art, the embodiment of the invention has the following beneficial effects:
the preparation method in the invention solves the problems of stickiness and agglomeration, low liquid preparation efficiency, more degradation and generation impurities and the like in the preparation process of the daptomycin liquid medicine by controlling the liquid medicine temperature, the pH value, the sequence of adding and dissolving materials and the like in the liquid preparation process and combining the optimization of the lyophilization parameters such as the prefreezing temperature, the sublimation temperature, the vacuum degree, the analysis drying thermometer time and the like, and has the advantages of less auxiliary materials, high lyophilization efficiency, good lyophilization quality, and obviously improved product quality and storage stability.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Examples 1 to 7
Daptomycin for injection, as shown in table 1, specifically comprises the following preparation steps:
(1) Taking water for injection, the total volume of which is 20-70%, stirring the water, and controlling the water temperature to be 2-8 ℃;
(2) Slowly adding a small amount of daptomycin in advance in a stirring state, and synchronously adding 0.1-3.0mol/L sodium hydroxide solution when the pH of the liquid medicine is reduced to 4.0, continuously adding daptomycin, and synchronously adjusting the pH value of the liquid medicine to be kept within the range of 4.0-7.0 until the daptomycin is completely dissolved;
(3) After the daptomycin is completely dissolved, regulating the end point pH value of the liquid medicine to be maintained at 4.0-7.0, and then adding water for injection to 1000mL;
(4) Filtering the liquid medicine into a buffer tank through a two-stage 0.22 mu m sterilizing filter, filling, and freeze-drying in a freeze dryer to obtain pale yellow loose blocks, wherein the freeze-drying process is as follows:
(1) precooling: feeding the box to the temperature of 0 ℃;
(2) pre-freezing: cooling to-45 ℃, and keeping for 3 hours;
(3) sublimation: starting a vacuum pump, vacuumizing to below 20Pa, heating to-5 ℃ at a constant speed of 15 ℃/h, and keeping for 12 hours:
(4) and (3) drying: heating to 25 ℃ at a constant speed of 25 ℃/h, and drying for 6 hours;
(5) and after the heat preservation is finished, vacuum plugging, re-pressing and discharging.
TABLE 1 Components and process parameters in examples 1-7 and comparative examples 1-6 of the present application
Comparative example 7
Daptomycin for injection specifically comprises the following preparation steps:
(1) Taking injection water with the total volume of 40%, starting stirring, and controlling the water temperature at 5 ℃;
(2) Adding 1mol/L sodium hydroxide solution in advance to adjust the pH to 10-12, and slowly adding 100g of daptomycin under stirring until the daptomycin is completely dissolved;
(3) After the daptomycin is completely dissolved, adjusting the pH value of the end point of the liquid medicine to 4.7, and then adding water for injection to 1000mL;
(4) Filtering the liquid medicine into a buffer tank through a two-stage 0.22 mu m sterilizing filter, filling, and freeze-drying in a freeze dryer, wherein the freeze-drying process is as follows:
(1) precooling: feeding the box to the temperature of 0 ℃;
(2) pre-freezing: cooling to-45 ℃, and keeping for 3 hours;
(3) sublimation: starting a vacuum pump, vacuumizing to below 20Pa, heating to-5 ℃ at a constant speed of 15 ℃/h, and keeping for 12 hours:
(4) and (3) drying: heating to 25 ℃ at a constant speed of 25 ℃/h, and drying for 6 hours;
(5) and after the heat preservation is finished, vacuum plugging, re-pressing and discharging.
Comparative examples 8 to 10
Daptomycin for injection, each step and each step use reagents and process parameters are the same as those of example 3, except that in step (4), as shown in table 2, the lyophilization process steps are as follows:
(1) precooling: feeding the box to the temperature of 0 ℃;
(2) pre-freezing: cooling to-20-45deg.C, and maintaining for 3 hr;
(3) sublimation: starting a vacuum pump, vacuumizing to below 20Pa, heating to-10 ℃ to 5 ℃ at a constant speed of 15 ℃/h, and keeping for 12-20 hours:
(4) and (3) drying: heating to 15-25deg.C at a constant speed of 25deg.C/h, and drying for 6 hr;
(5) and after the heat preservation is finished, vacuum plugging, re-pressing and discharging.
Table 2-lyophilization process parameters in comparative examples 8-10 of the present application
| Project | Prefreezing temperature | Prefreezing time | Sublimation temperature | Sublimation time | Drying temperature | Drying time |
| Comparative example 8 | -20℃ | 3 hours | -5℃ | For 12 hours | 25℃ | For 6 hours |
| Comparative example 9 | -45℃ | 3 hours | -10℃ | 20 hours | 25℃ | For 6 hours |
| Comparative example 10 | -45℃ | 3 hours | -5℃ | For 12 hours | 15℃ | For 6 hours |
TABLE 3 liquid preparation times for examples 1-7 and comparative examples 1-10
Performance test
1. Stability investigation: the HPLC is adopted to detect the lactone hydrolysate, the beta isomer and the dehydrated daptomycin content in different time after the samples of the examples and the comparative examples are redissolved, the redissolved mode is to dissolve 500mg of the samples by adopting 10mL of 0.9% sodium chloride, and the detection time is respectively 0h, 4h, 8h, 12h, 16h, 20h and 24h:
1) Test solution: samples of examples and comparative examples were taken, dissolved in the mobile phase and diluted to about 1.0mg per 1ml of solution;
2) Control solution: precisely measuring 1mL of the sample solution, placing the sample solution into a 100mL measuring flask, diluting the sample solution to a scale with a diluent, and shaking the sample solution uniformly;
3) Chromatographic conditions: chromatographic column: phenomnex IB-Sil C8 column, 5 μm, 250X 4.6mm; mobile phase: monoammonium phosphate solution-acetonitrile at ph3.25 (67:33); detection wavelength: 214nm; flow rate: 1.5ml/min; sample injection volume: 20 μl;
4) The test steps are as follows: and precisely measuring 20 mu L of the sample solution, injecting the sample solution into a liquid chromatograph, calculating the content of each impurity according to a self-contrast method when impurity peaks exist in the chromatogram of the sample solution, and obtaining the results shown in tables 4-5.
2. Freeze-drying effect detection: the test methods of the finished products of the examples and comparative examples with respect to lyophilization phenomenon, acidity, moisture and reconstitution time properties are shown below, and the test results are shown in table 6:
1) Lyophilization phenomenon: visual inspection of the lyophilized product;
2) Acidity: detecting according to the standard 0631 of the four general rules of the 2020 edition of Chinese pharmacopoeia;
3) Moisture content: detecting according to the first method (Fei Xiushi method) standard of the four-part general rule 0832 of the 2020 edition of Chinese pharmacopoeia;
4) And (3) redissolving time: taking 500mg of sample of the example or the comparative example, slowly adding 10mL of 0.9% sodium chloride injection on the wall of the bottle by adopting a syringe needle, lightly rotating the bottle to ensure that the powder is completely immersed, lightly rotating or shaking the bottle for a plurality of minutes until the solution is completely dissolved, and recording the re-dissolution time.
TABLE 4 results of 24-hour stability study of the medicinal solutions of examples 1-7 of the present application
TABLE 5 results of 24 hour stability study of the medicinal solutions of comparative examples 1 to 7 of the present application
TABLE 6 freeze drying Effect test of examples 1-5 and comparative examples 1-10 of the present application
As can be seen from the performance test results in combination with tables 4 to 5, compared with comparative examples 1 to 7, the pH, the liquid preparation temperature, the sodium hydroxide concentration and the daptomycin concentration in the liquid medicine preparation process of examples 1 to 7 are controlled, and the prepared daptomycin liquid medicine has no obvious increase of main degradation impurities within 24 hours under different storage time, thus indicating that the liquid medicine has higher stability.
The concentration of the sodium hydroxide solution for adjusting the pH value of the liquid medicine is increased to 4.0mol/L in comparative example 1, the end pH value of the liquid medicine is increased to 8.0 in comparative example 2, and the sodium hydroxide solution is added first and then daptomycin is added for dissolution in the preparation of the liquid medicine in comparative example 7, so that the impurity lactone hydrolysate and beta isomer are obviously increased; both comparative examples 3 and 4 increased the formulation temperature of the liquid medicine in step (1) to 15-25 ℃, resulting in a significant increase in impurity dehydrated daptomycin. Therefore, in the process of preparing the liquid medicine, the concentration of the sodium hydroxide solution is controlled to be between 0.1 and 3.0mol/L, the temperature of the liquid medicine is controlled to be between 2 and 8 ℃, the pH value of the final liquid medicine is controlled to be between 4.0 and 7.0, the degradation impurities can be prevented from being obviously increased within 24 hours of storage of the liquid medicine, and the storage stability of the liquid medicine is improved.
Meanwhile, during the preparation of the liquid medicine, the higher the pH value of the liquid medicine is, the faster the dissolution rate of the daptomycin is, the shorter the preparation time is, but the main degradation impurities (lactone hydrolysate) are increased along with the increase of the pH value, and the process selection of the embodiment 3 can obtain the daptomycin for injection with lower impurities and short preparation time in the range of acceptable impurity degradation rate comprehensively considered.
As can be seen from the performance test results of example 3 and comparative examples 5-6 in Table 6, when the concentration of daptomycin in the lyophilized liquid medicine is too high or too low, the lyophilization effect is poor, the block products are atrophic and layered or cracked, and when the concentration of daptomycin is too low, the water content of the lyophilized products is large and the reconstitution time is long.
As can be seen from the combination of the lyophilization process parameters of comparative examples 8 to 10 in Table 2 and the performance test results in Table 6, the lyophilization process parameters, when the temperatures of pre-lyophilization, sublimation and analytical drying are too high or too low, result in poor lyophilization effect and prolonged lyophilization time, and the partial products thereof have atrophy and delamination phenomena, and the lyophilized products have larger water content and longer reconstitution time.
The foregoing embodiments have been provided for the purpose of illustrating the general principles of the present invention, and are not to be construed as limiting the scope of the invention. It should be noted that any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art without departing from the spirit and principles of the present invention are intended to be included in the scope of the present invention.
Claims (3)
1. The preparation method of the daptomycin for injection is characterized by comprising the following steps:
(1) Preparing part of water, and controlling the water temperature to be 2-8 ℃;
(2) Slowly adding a small amount of daptomycin in advance in a stirring state, and synchronously adding a pH regulator with the concentration of 0.1-3.0mol/L when the pH of the liquid medicine is reduced to below 4.0, wherein the pH regulator is a sodium hydroxide solution, the daptomycin is continuously added, and the pH value of the liquid medicine is synchronously regulated to be kept within the range of 4.0-7.0 until the daptomycin is completely dissolved, and the total added weight of the daptomycin is 50-100 parts;
(3) After the daptomycin is completely dissolved, regulating the end point pH value of the liquid medicine to be maintained at 4.0-7.0, and then adding water to 1000 parts of the total weight;
(4) Filtering the liquid medicine, filling, and freeze-drying in a freeze-drying device to obtain pale yellow loose block;
in the step (1), the total volume of the water for preparation is 20% -70%;
in step (4), the lyophilization process comprises the steps of:
s01, precooling: the temperature of the box entering is 0-5 ℃;
s02, pre-freezing: cooling to-30 to-45 ℃ and keeping for 2-4 hours;
s03, sublimating: starting a vacuum pump, vacuumizing to below 20Pa, heating to-5 ℃ to 0 ℃ at a constant speed of 15-20 ℃/h, and keeping for 10-15 hours:
s04, drying: heating to 20-25 ℃ at a constant speed of 20-25 ℃/h, and drying for 4-8 hours;
s05, after heat preservation is finished, vacuum plugging, re-pressing and discharging.
2. The method of claim 1, wherein in step (4), the medicinal solution is filtered through a two-stage 0.22 μm sterilizing filter.
3. The method for preparing daptomycin for injection according to claim 1, wherein in the step (3), the final pH of the medicinal liquid is adjusted to 4.0-5.0.
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Citations (6)
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|---|---|---|---|---|
| CA2752784A1 (en) * | 2010-09-21 | 2012-03-21 | Xellia Pharmaceuticals Aps | Daptomycin formulation |
| US20170348382A1 (en) * | 2014-12-16 | 2017-12-07 | Dr. Reddy's Laboratories Limited | Lyophilized injectable compositions of daptomycin |
| US20180177843A1 (en) * | 2012-09-11 | 2018-06-28 | Hospira Australia Pty Ltd | Daptomycin formulations and uses thereof |
| CN110548130A (en) * | 2018-06-04 | 2019-12-10 | 浙江医药股份有限公司新昌制药厂 | daptomycin-containing spray dry powder and industrial preparation method thereof |
| CN114344447A (en) * | 2021-12-16 | 2022-04-15 | 华北制药股份有限公司 | Daptomycin for injection and preparation method thereof |
| CN114788814A (en) * | 2021-01-26 | 2022-07-26 | 浙江创新生物有限公司 | High-stability daptomycin composition for injection and preparation method and application thereof |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2752784A1 (en) * | 2010-09-21 | 2012-03-21 | Xellia Pharmaceuticals Aps | Daptomycin formulation |
| US20180177843A1 (en) * | 2012-09-11 | 2018-06-28 | Hospira Australia Pty Ltd | Daptomycin formulations and uses thereof |
| US20170348382A1 (en) * | 2014-12-16 | 2017-12-07 | Dr. Reddy's Laboratories Limited | Lyophilized injectable compositions of daptomycin |
| CN110548130A (en) * | 2018-06-04 | 2019-12-10 | 浙江医药股份有限公司新昌制药厂 | daptomycin-containing spray dry powder and industrial preparation method thereof |
| CN114788814A (en) * | 2021-01-26 | 2022-07-26 | 浙江创新生物有限公司 | High-stability daptomycin composition for injection and preparation method and application thereof |
| CN114344447A (en) * | 2021-12-16 | 2022-04-15 | 华北制药股份有限公司 | Daptomycin for injection and preparation method thereof |
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