WO2022147932A1 - 一种注射用磷酸特地唑胺冻干制剂的制备方法 - Google Patents
一种注射用磷酸特地唑胺冻干制剂的制备方法 Download PDFInfo
- Publication number
- WO2022147932A1 WO2022147932A1 PCT/CN2021/091269 CN2021091269W WO2022147932A1 WO 2022147932 A1 WO2022147932 A1 WO 2022147932A1 CN 2021091269 W CN2021091269 W CN 2021091269W WO 2022147932 A1 WO2022147932 A1 WO 2022147932A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- freeze
- preparation
- tedizolid phosphate
- injection
- dried
- Prior art date
Links
- 229960003947 tedizolid phosphate Drugs 0.000 title claims abstract description 72
- 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 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 56
- 238000002347 injection Methods 0.000 title claims abstract description 32
- 239000007924 injection Substances 0.000 title claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000007788 liquid Substances 0.000 claims abstract description 17
- 238000004108 freeze drying Methods 0.000 claims abstract description 13
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 10
- 239000008215 water for injection Substances 0.000 claims abstract description 9
- 239000003223 protective agent Substances 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 38
- 239000000243 solution Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000013078 crystal Substances 0.000 description 9
- 230000008569 process Effects 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000002788 crimping Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000013505 freshwater Substances 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000000859 sublimation Methods 0.000 description 3
- 230000008022 sublimation Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 241000192125 Firmicutes Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 2
- 229960003907 linezolid Drugs 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 108010077805 Bacterial Proteins Proteins 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 201000000297 Erysipelas Diseases 0.000 description 1
- 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 1
- 208000037942 Methicillin-resistant Staphylococcus aureus infection Diseases 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000004781 supercooling Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229960003879 tedizolid Drugs 0.000 description 1
- 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 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
Definitions
- the scheme relates to a preparation method of a freeze-dried preparation of tedizolid phosphate for injection, which belongs to the field of pharmaceutical preparations.
- ABSSSI Acute bacterial skin and skin tissue infections
- MRSA Methicillin-resistant Staphylococcus aureus
- CA-MRSA Community-acquired MRSA
- Tedizolid phosphate can be converted into tedizolid with antibacterial activity by endogenous phosphatase, and then combined with bacterial ribosomal 50S subunit, thereby inhibiting bacterial protein synthesis, showing broad-spectrum resistance to Gram-positive bacteria in vitro activity and covered MRSA and vancomycin- or linezolid-resistant strains.
- tedizolid phosphate has the advantages of non-inferiority, shorter treatment period, lower dose and better patient compliance.
- the currently available tedizolid phosphate formulations are tablet and lyophilized for injection.
- this scheme provides a kind of tedizolid phosphate freeze-dried preparation.
- a preparation method is provided to solve the above-mentioned problems existing in the preparation process of the tedizolid phosphate freeze-dried preparation.
- a first aspect of the present application provides a method for preparing a freeze-dried preparation of tedizolid phosphate for injection, comprising the following process steps:
- the freeze-dried product is heated to -30 to -10°C at a rate of 0.8 to 1.2°C/min for 1000 to 1100min; continue to be heated to 40 to 50°C at a rate of 0.8 to 1.2°C/min.
- the temperature is maintained for 240-260 min to obtain the lyophilized preparation of tedizolid phosphate for injection.
- step a the mass ratio of described water for injection and described tedizolid phosphate is 8 ⁇ 12:1.
- the alkali solution is a sodium hydroxide solution of 0.5 to 2 mol/L.
- the freeze-drying protective agent is mannitol, and the addition amount is equivalent to 45-55% of the quality of the tedizolid phosphate.
- the reagent used for adjusting the pH is sodium hydroxide solution or hydrochloric acid.
- the pH is higher than the preset pH, it is adjusted with hydrochloric acid; when the pH is lower than the preset pH, it is adjusted with sodium hydroxide solution.
- step a the pH is adjusted to 7.7 ⁇ 7.8.
- the vacuum condition is 400-500 mtorr.
- This scheme also provides a freeze-dried preparation of tedizolid phosphate for injection prepared by the method for preparing the freeze-dried preparation of tedizolid phosphate for injection.
- the preparation method of the existing Tedizolid Phosphate freeze-dried preparation for injection is to freeze and heat up the Tedizolid Phosphate liquid in turn to obtain a freeze-dried product.
- the process takes 2500-5800min, and only the analysis and drying time reaches 1000- 2500min.
- three cooling and three heating processes are interspersed.
- the tedizolid phosphate liquid is cooled to -8 ⁇ -10 °C for 25-35min, which can accumulate more energy in the liquid and reduce the supercooling temperature; continue to cool the liquid to -40 ⁇ - Keep it at 50°C for 35 ⁇ 45min to form freeze-dried crystals with special characteristics including a large number of ice crystals; then heat up to -15 ⁇ -10°C for 50 ⁇ 70min, and anneal, so that the small ice crystal molecules in the freeze-dried crystals can be converted to large ice crystals Molecular migration forms more water sublimation channels; then cooled to -40 ⁇ -50°C for 80 ⁇ 100min, the large ice crystal molecules can be re-lyophilized to form a stable glass state; then heated to -30 ⁇ -10°C, keep it for 1000 ⁇ 1100min, you can get a freeze-dried product with a specific form containing many water sublimation channels.
- the final heating and desorption drying time of the freeze-dried product is shortened from the traditional 1000-2500min to 250min, the whole preparation process takes no more than 1300min, and the preparation process is simple and significant.
- the time cost and labor cost for preparing the freeze-dried preparation of tedizolid phosphate for injection are reduced.
- the freeze-dried preparation of tedizolid phosphate for injection obtained by final analysis and drying forms a larger and uniform crystal form, which significantly improves the quality of the freeze-dried preparation of tedizolid phosphate for injection.
- the cooling and heating process at the above cooling and heating rate can form a large number of uniform water sublimation channels in the freeze-dried product, thereby effectively shortening the analysis and drying time of the freeze-dried product.
- the lyophilization steps in the lyophilizer after the tedizolid phosphate liquid is subpackaged are as follows:
- the lyophilization steps in the lyophilizer after the tedizolid phosphate liquid is subpackaged are as follows:
- the lyophilization steps in the lyophilizer after the tedizolid phosphate liquid is subpackaged are as follows:
- Example 2 and Example 3 The content of each related substance in Example 2 and Example 3 is substantially equivalent to that in Example 1, wherein the total impurity content in the tedizolid phosphate freeze-dried preparation finished product for injection obtained in Example 2 is 0.33%, and the moisture content is 1.28%; the total impurity content in the tedizolid phosphate freeze-dried preparation finished product for injection obtained in Example 3 is 0.29%, and the moisture content is 1.30%.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种注射用磷酸特地唑胺冻干制剂的制备方法，包括以下步骤：a、向注射用水中加入磷酸特地唑胺和冻干保护剂，得到磷酸特地唑胺药液；b、将药液依次冷却至-8～-10℃和-40～-50℃，保持特定时间；然后升温至-15～-10℃，再冷却至-40～-50℃，保持特定时间，得到冻干品；c、在真空条件下，将冻干品升温至-30～-10℃和40～50℃，保持特定时间即得。根据该制备方法得到的注射用磷酸特地唑胺冻干制剂。
Description
本申请要求于2021年01月08日提交的中国专利申请CN202110023135.X的优先权。在先申请的内容通过整体引用并入本申请。
本方案涉及注射用磷酸特地唑胺冻干制剂的制备方法，属于药物制剂领域。
急性细菌性皮肤和皮肤组织感染(ABSSSI)，包括蜂窝组织炎、丹毒、皮肤脓肿以及伤口感染，因危及生命而需要手术或入院治疗。研究发现，越来越多的ABSSSIs是由耐药性致病原引起，同时一些抗菌剂因其副作用而限制了自身的使用。革兰阳性菌(多数为金黄色葡萄球菌以及溶血性链球菌)是引起ABSSSI的主要病原体。耐甲氧西林的金黄色葡萄菌(MRSA)如今在一些欧洲国家、美国等地也开始蔓延。社区获得性MRSA(CA-MRSA)现已成为引起皮肤及软组织感染的主要病原体，该类感染治疗失败率和复发率都极高，从而严重威胁公共卫生安全。虽然目前有一些治疗MRSA感染的用药方案，但可用药物有限，使临床治疗ABSSSI仍面临着诸多挑战，如药物间的相互作用、用药剂量调整、安全性以及耐药性等问题。因此，临床迫切需要新型抗生素用来治疗急性细菌性皮肤及其附属结构的感染。
磷酸特地唑胺可通过内源性磷酸酶转化为具有抗菌活性的特地唑胺，再与细菌核糖体50S亚基结合，进而抑制细菌蛋白合成，在体外试验中表现出广谱抗革兰阳性菌的活性，并覆盖了MRSA及耐万古霉素或利奈唑胺的菌株。磷酸特地唑胺与利奈唑胺相比具有非劣效性、治疗周期短、使用剂量小和患者依从性好等优势。目前出现的磷酸特地唑胺药剂有片剂和注射用冻干剂型。其中磷酸特地唑胺冻干制剂的冻干工艺极其复杂，存在耗时长、晶型大小不均、杂质含量高和制备成本高等缺陷，影响注射用特地唑胺冻干制剂的推广使用。
针对现有磷酸特地唑胺冻干制剂制备过程中存在的工艺复杂、耗时长、晶型大小不均、杂质含量高和制备成本高的问题，本方案提供一种磷酸特地唑胺冻干制剂的制备方法，以解决磷酸特地唑胺冻干制剂制备过程中存在的上述问题。
本申请的第一方面提供一种注射用磷酸特地唑胺冻干制剂的制备方法，包括以下工艺步骤：
a、向注射用水中加入磷酸特地唑胺，滴加碱液至磷酸特地唑胺溶解，加入冻干保护剂，调节pH，得到磷酸特地唑胺药液；
a、向注射用水中加入磷酸特地唑胺，滴加碱液至磷酸特地唑胺溶解，加入冻干保护剂，调节pH，得到磷酸特地唑胺药液；
b、将所述磷酸特地唑胺药液冷却至-8~-10℃保持25-35min，继续冷却至-40~-50℃保持35~45min；然后升温至-15~-10℃保持50~70min；再冷却至-40~-50℃保持80~100min，得到冻干品；所述冷却和所述升温的速度均为0.8~1.2℃/min；
c、在真空条件下，将所述冻干品以0.8~1.2℃/min的速度升温至-30~-10℃保持1000~1100min；继续以0.8~1.2℃/min的速度升温至40~50℃保持240~260min，得到所述注射用磷酸特地唑胺冻干制剂。
作为本方案的一个实施例，步骤a中，所述注射用水与所述磷酸特地唑胺的质量比为8~12:1。
作为本方案的一个实施例，步骤a中，所述碱液为0.5~2mol/L的氢氧化钠溶液。
作为本方案的一个实施例，步骤a中，所述冻干保护剂为甘露醇，加入量相当于所述磷酸特地唑胺质量的45~55%。
上述优选的特定量的甘露醇的加入，可以保证磷酸特地唑胺在多次升温和降温的冻干过程中保持稳定的活性。
作为本方案的一个实施例，步骤a中，调节所述pH所用的试剂为氢氧化钠溶液或盐酸。当pH高于预设pH时，用盐酸进行调节；当pH低于预设pH时，用氢氧化钠溶液进行调节。
作为本方案的一个实施例，步骤a中，调解所述pH至7.7~7.8。
作为本方案的一个实施例，步骤c中，所述真空条件为400~500毫托。
本方案还提供了利用所述注射用磷酸特地唑胺冻干制剂的制备方法制备得到的注射用磷酸特地唑胺冻干制剂。
与现有技术相比，本方案具有如下优点：
现有的注射用磷酸特地唑胺冻干制剂的制备方法是将磷酸特地唑胺药液依次进行冷冻和升温，得到冻干产品，该过程用时在2500-5800min，仅解析干燥时间就达到1000-2500min。而本方案提供的注射用磷酸特地唑胺冻干制剂的制备方法中穿插设置了三次降温和三次升温过程。其中，将磷酸特地唑胺药液冷先却至-8~-10℃保持25-35min，可以在药液中聚集较大能量、减小过冷温度；继续将药液冷却至-40~-50℃保持35~45min，形成包含大量冰晶的特殊性状的冻干结晶；然后升温至-15~-10℃保持50~70min，进行退火，可使上述冻干结晶中的小冰晶分子向大冰晶分子迁移形成较多的水分升华通道；再冷却至-40~-50℃保持80~100min，可以将大冰晶分子重新进行冻干，形成稳定的玻璃态；再在真空条件下升温至-30~-10℃，保持1000~1100min，可得到包含众多水分升华通道的特定形态的冻干品。通过控制上述降温和升温过程中的终点温度和保持时间，使冻干品最终的升温解析干燥时间由传统的1000-2500min缩短为250min，整个制备过程用时不超过1300min，且制备过程操作简单，显著降低了制备注射用磷酸特地唑胺冻干制剂的时间成本和人工成本。同时，通过设置三次降温和三次升温过程使最终解析干燥得到的注射用磷酸特地唑胺冻干制剂形成较大且均匀的晶型，显著提高了注射用磷酸特地唑胺冻干制剂的质量。
以上述冷却和升温速度进行冷却和升温过程可以在冻干产品中形成大量均匀的水分升华通道，进而有效缩短冻干品的解析干燥时间。
本申请的实施方式
实施例1
取的新鲜注射用水500mL于烧杯中，投入126g的磷酸特地唑胺，滴加1mol/L的氢氧化钠溶液至磷酸特地唑胺完全溶解，加入63g的甘露醇，测定pH，用1mol/L的氢氧化钠调节pH至7.7，加入注射用水定容至1260mL，混合均匀，得到磷酸特地唑胺药液。按照2.5ml/支装量进行灌装，灌装500支，半加塞移入冻干机内。
磷酸特地唑胺药液分装后在冻干机内的冻干步骤如下：
将磷酸特地唑胺药液以1℃/min的速度冷却至-9℃保持30min，继续以1℃/min的速度冷却至-45℃保持40min；然后以1℃/min的速度升温至-12℃保持60min；再以1℃/min的速度冷却至-45℃保持90min，得到冻干品；此时冻干机中的腔室排空至真空度达到400毫托，将冻干品以1℃/min的速度升温至-20℃保持1000min；继续以1℃/min的速度升温至45℃保持250min，得到注射用磷酸特地唑胺冻干制剂，压塞，进气出箱，用铝塑组合盖轧口。
实施例2
取的新鲜注射用水500mL于烧杯中，投入125g的磷酸特地唑胺，滴加0.5mol/L的氢氧化钠溶液至磷酸特地唑胺完全溶解，加入57g的甘露醇，测定pH，用0.5mol/L的氢氧化钠调节pH至7.8，加入注射用水定容至1000mL，混合均匀，得到磷酸特地唑胺药液。按照2ml/支装量进行灌装，灌装500支，半加塞移入冻干机内。
磷酸特地唑胺药液分装后在冻干机内的冻干步骤如下：
将磷酸特地唑胺药液以0.8℃/min的速度冷却至-8℃保持25min，继续以0.8℃/min的速度冷却至-40℃保持35min；然后以0.8℃/min的速度升温至-15℃保持50min；再以0.8℃/min的速度冷却至-40℃保持80min，得到冻干品；此时冻干机中的腔室排空至真空度达到500毫托，将冻干品以0.8℃/min的速度升温至-30℃保持1100min；继续以0.8℃/min的速度升温至40℃保持240min，得到注射用磷酸特地唑胺冻干制剂，压塞，进气出箱，用铝塑组合盖轧口。
实施例3
取的新鲜注射用水500mL于烧杯中，投入200g的磷酸特地唑胺，滴加2mol/L的氢氧化钠溶液至磷酸特地唑胺完全溶解，加入110g的甘露醇，测定pH，用1mol/L的盐酸调节pH至7.7，加入注射用水定容至2400mL，混合均匀，得到磷酸特地唑胺药液。按照3ml/支装量进行灌装，灌装800支，半加塞移入冻干机内。
磷酸特地唑胺药液分装后在冻干机内的冻干步骤如下：
将磷酸特地唑胺药液以1.2℃/min的速度冷却至-10℃保持35min，继续以1.2℃/min的速度冷却至-50℃保持45min；然后以1.2℃/min的速度升温至-10℃保持70min；再以1.2℃/min的速度冷却至-50℃保持100min，得到冻干品；此时冻干机中的腔室排空至真空度达到500毫托，将冻干品以1.2℃/min的速度升温至-10℃保持1100min；继续以1.2℃/min的速度升温至50℃保持260min，得到注射用磷酸特地唑胺冻干制剂，压塞，进气出箱，用铝塑组合盖轧口。
检测实施例1-3得到的注射用磷酸特地唑胺冻干制剂成品与原研样品中的有关物质，检测结果如下表所示：
实施例2和实施例3中各有关物质的含量与实施例1中的基本相当，其中实施例2得到的注射用磷酸特地唑胺冻干制剂成品中的总杂质含量为0.33%，水分含量为1.28%；实施例3得到的注射用磷酸特地唑胺冻干制剂成品中的总杂质含量为0.29%，水分含量为1.30%。
通过检验结果对比可知按照本方案的方法所得注射用磷酸特地唑胺冻干制剂产品的性状与原研保持一致，有关物质和水分含量明显优于原研产品。
以上所述仅为本方案的较佳实施例而已，并不用以限制本方案，凡在本方案的精神和原则之内所作的任何修改、等同替换或改进等，均应包含在本方案的保护范围之内。
Claims (8)
- 一种注射用磷酸特地唑胺冻干制剂的制备方法，其特征在于：包括以下工艺步骤：a、向注射用水中加入磷酸特地唑胺，滴加碱液至磷酸特地唑胺溶解，加入冻干保护剂，调节pH，得到磷酸特地唑胺药液；b、将所述磷酸特地唑胺药液冷却至-8~-10℃保持25-35min，继续冷却至-40~-50℃保持35~45min；然后升温至-15~-10℃保持50~70min；再冷却至-40~-50℃保持80~100min，得到冻干品；所述冷却和所述升温的速度均为0.8~1.2℃/min；c、在真空条件下，将所述冻干品以0.8~1.2℃/min的速度升温至-30~-10℃保持1000~1100min；继续以0.8~1.2℃/min的速度升温至40~50℃保持240~260min，得到所述注射用磷酸特地唑胺冻干制剂。
- 如权利要求1所述的注射用磷酸特地唑胺冻干制剂的制备方法，其特征在于：步骤a中，所述注射用水与所述磷酸特地唑胺的质量比为8~12:1。
- 如权利要求1所述的注射用磷酸特地唑胺冻干制剂的制备方法，其特征在于：步骤a中，所述碱液为0.5~2mol/L的氢氧化钠溶液。
- 如权利要求1所述的注射用磷酸特地唑胺冻干制剂的制备方法，其特征在于：步骤a中，所述冻干保护剂为甘露醇，加入量相当于所述磷酸特地唑胺质量的45~55%。
- 如权利要求1所述的注射用磷酸特地唑胺冻干制剂的制备方法，其特征在于：步骤a中，调节所述pH所用的试剂为氢氧化钠溶液或盐酸。
- 如权利要求1所述的注射用磷酸特地唑胺冻干制剂的制备方法，其特征在于：步骤a中，调解所述pH至7.7~7.8。
- 如权利要求1所述的注射用磷酸特地唑胺冻干制剂的制备方法，其特征在于：步骤c中，所述真空条件为400~500毫托。
- 利用权利要求1~7任一项所述的注射用磷酸特地唑胺冻干制剂的制备方法制备得到的注射用磷酸特地唑胺冻干制剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110023135.XA CN112826801B (zh) | 2021-01-08 | 2021-01-08 | 一种注射用磷酸特地唑胺冻干制剂的制备方法 |
| CN202110023135.X | 2021-01-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022147932A1 true WO2022147932A1 (zh) | 2022-07-14 |
Family
ID=75928628
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2021/091269 WO2022147932A1 (zh) | 2021-01-08 | 2021-04-30 | 一种注射用磷酸特地唑胺冻干制剂的制备方法 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN112826801B (zh) |
| WO (1) | WO2022147932A1 (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112826801B (zh) * | 2021-01-08 | 2022-03-29 | 石家庄四药有限公司 | 一种注射用磷酸特地唑胺冻干制剂的制备方法 |
| CN114246832A (zh) * | 2021-12-31 | 2022-03-29 | 四川制药制剂有限公司 | 一种注射用磷酸特地唑胺及制备方法 |
| CN114805439A (zh) * | 2022-05-07 | 2022-07-29 | 四川制药制剂有限公司 | 一种磷酸特地唑胺片及其制备方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105287407A (zh) * | 2015-11-24 | 2016-02-03 | 南京正大天晴制药有限公司 | 一种注射用磷酸特地唑胺 |
| CN107375220A (zh) * | 2017-07-21 | 2017-11-24 | 苏州信恩医药科技有限公司 | 一种磷酸特地唑胺冻干粉针剂及其制备方法 |
| CN112826801A (zh) * | 2021-01-08 | 2021-05-25 | 石家庄四药有限公司 | 一种注射用磷酸特地唑胺冻干制剂的制备方法 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105640899A (zh) * | 2014-11-12 | 2016-06-08 | 天津市汉康医药生物技术有限公司 | 供注射用泰地唑胺药物组合物 |
| CN106344525A (zh) * | 2016-11-08 | 2017-01-25 | 天津红日药业股份有限公司 | 一种磷酸泰地唑胺冻干粉针 |
-
2021
- 2021-01-08 CN CN202110023135.XA patent/CN112826801B/zh active Active
- 2021-04-30 WO PCT/CN2021/091269 patent/WO2022147932A1/zh active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105287407A (zh) * | 2015-11-24 | 2016-02-03 | 南京正大天晴制药有限公司 | 一种注射用磷酸特地唑胺 |
| CN107375220A (zh) * | 2017-07-21 | 2017-11-24 | 苏州信恩医药科技有限公司 | 一种磷酸特地唑胺冻干粉针剂及其制备方法 |
| CN112826801A (zh) * | 2021-01-08 | 2021-05-25 | 石家庄四药有限公司 | 一种注射用磷酸特地唑胺冻干制剂的制备方法 |
Non-Patent Citations (2)
| Title |
|---|
| CAI ZIYANG: "Design and Optimization Principles of Pharmaceutical Freeze Drying Process", SEEK MEDICAL AND ASK THE MEDICINE, vol. 10, no. 12, 1 December 2012 (2012-12-01), pages 235 - 235, XP055949486, ISSN: 1672-2523 * |
| LIU YINI, ET AL.: "Research on Pharmaceutical Freeze Drying Technology and Process", HEILONGJIANG SCIENCE AND TECHNOLOGY INFORMATION, no. 8, 23 April 2007 (2007-04-23), pages 181 - 181, XP055949485 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112826801A (zh) | 2021-05-25 |
| CN112826801B (zh) | 2022-03-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2022147932A1 (zh) | 一种注射用磷酸特地唑胺冻干制剂的制备方法 | |
| CN101224196A (zh) | 一种盐酸氨溴索冻干粉针及其制备方法 | |
| CN105287407B (zh) | 一种注射用磷酸特地唑胺 | |
| CA3010565C (en) | Freeze-dried formulations of antibacterial protein | |
| CN101856335B (zh) | 注射用阿奇霉素组合物冻干粉针 | |
| CN103735512A (zh) | 一种恩诺沙星固体分散体及其制备方法 | |
| JP2024521274A (ja) | 高安定性の注射用ダプトマイシン組成物、その調製方法及びその適用 | |
| CN111588859B (zh) | 一种冻干保护剂及其应用和冻干苗及其制备方法 | |
| CN102743342B (zh) | 一种供注射用夫西地酸钠冻干组合物 | |
| CN111840236B (zh) | 一种注射用美罗培南丙磺舒钠复方冻干制剂 | |
| CN103893776B (zh) | 羊传染性脓疱病毒细胞弱毒疫苗耐热冻干保护剂及其制备方法和应用 | |
| CN108635333B (zh) | 一种盐酸沃尼妙林冻干粉针剂及其制备方法 | |
| CN104983685A (zh) | 一种阿莫西林可溶性粉及其制备方法 | |
| CN106310244A (zh) | 一种注射用门冬酰胺酶的冻干工艺 | |
| CN116763744B (zh) | 一种注射用氯诺昔康的冻干工艺 | |
| CN112076162A (zh) | 一种注射用哌拉西林钠他唑巴坦钠丙磺舒钠三方冻干制剂 | |
| CN107982261B (zh) | 一种艾司奥美拉唑钠冻干粉及其制备方法 | |
| CN101721378B (zh) | 盐酸头孢甲肟冻干粉针的制备方法 | |
| CN117679376A (zh) | 一种注射用磷酸特地唑胺制剂的制备方法 | |
| CN111419804A (zh) | 一种注射用血管生成抑肽冻干制剂及其冻干方法 | |
| CN115212223A (zh) | 一种注射用阿奇霉素组合物及其制备工艺 | |
| CN101422438A (zh) | 一种不含辅料的复方二氯醋酸二异丙胺冻干制剂及制备工艺 | |
| CN112691083B (zh) | 盐酸万古霉素的冻干工艺 | |
| CN109394706A (zh) | 一种注射用兰索拉唑冻干粉及其制备方法 | |
| CN116712394B (zh) | 一种注射用乳糖酸克拉霉素制剂及其工艺、用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21916982 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 21916982 Country of ref document: EP Kind code of ref document: A1 |