WO2014000144A1 - 头孢噻肟钠和舒巴坦钠的复方制剂及其制备方法和应用 - Google Patents

头孢噻肟钠和舒巴坦钠的复方制剂及其制备方法和应用 Download PDF

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WO2014000144A1
WO2014000144A1 PCT/CN2012/077443 CN2012077443W WO2014000144A1 WO 2014000144 A1 WO2014000144 A1 WO 2014000144A1 CN 2012077443 W CN2012077443 W CN 2012077443W WO 2014000144 A1 WO2014000144 A1 WO 2014000144A1
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sodium
cefotaxime
sulbactam
preparation
compound preparation
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PCT/CN2012/077443
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English (en)
French (fr)
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孙天宇
王海勇
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北京新天宇科技开发有限公司
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Priority to PCT/CN2012/077443 priority Critical patent/WO2014000144A1/zh
Publication of WO2014000144A1 publication Critical patent/WO2014000144A1/zh

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the present invention relates to the field of pharmaceutical compound preparations, and in particular to a compound preparation of cefotaxime sodium and sulbactam sodium, and a preparation method and application thereof. Background technique
  • the invention relates to a compound preparation of cefotaxime sodium and sulbactam sodium, which is a medicine composition for treating a stable active ingredient of a drug-resistant bacteria such as NDM-1 "super bacteria".
  • NDM-1 is the English abbreviation of New Delhi metallo- ⁇ -lactamase-1, published in the famous British medical journal The Infectious Diseases on August 11, 2010.
  • Tim Walsh who published the University of Cambridge in the UK, named the superbug "New Delhi Metalloproteinase-1", because the bacteria carrying the gene produced a special beta-lactamase and was active.
  • the metal ion was first appeared in the Indian capital of New Delhi, hence the name: NDM-1.
  • the bacteria producing NDM-1 are mainly Escherichia coli and Klebsiella pneumoniae. These bacteria can cause both nosocomial infections and community infections, including urinary tract infections, bloodstream infections, pneumonia, catheter-related infections, and wounds. Infection, etc. Nearly 200 kinds of antibiotics in the world are almost incapable of this new type of super bacteria (Family et al., "Super Bacteria" NDM-1 discovery and research progress. Foreign Medicine Antibiotics, 2011, 32 (6): 253-8) . Therefore, it is urgent to find a drug that can effectively inhibit the infection of resistant bacteria such as NDM-1 "super bacteria".
  • Cefotaxime sodium is a third-generation cephalosporin semi-synthetic broad-spectrum antibiotic. It has the advantages of broad antibacterial spectrum, strong antibacterial effect and small side effects. It is widely used in the treatment of sepsis caused by sensitive bacteria, purulent meningitis and infections of the respiratory tract, urinary tract, biliary tract, bones and joints, skin and soft tissues, abdominal cavity, digestive tract, facial features, genitals, etc., and can also be used for immune function. Treatment of infectious diseases with low defense and low defense functions such as decreased antibody cells.
  • Cefotaxime sodium is more stable to ⁇ -lactamase when it is initially applied.
  • the cefotaxime sodium bacteria have increased year by year, especially the extended spectrum ⁇ -lactamase produced by Escherichia coli, Salmonella typhi, Klebsiella pneumoniae, Proteus vulgaris, etc., which are mediated by plasmids and can be effectively hydrolyzed.
  • Cefotaxime sodium poses great difficulties in the clinical treatment of infectious diseases.
  • the drug resistance gene can be transferred to the plasmid through different transfer elements, allowing the drug resistance gene to spread over a wide range.
  • cefotaxime and sulbactam are actually used.
  • the combination of cefotaxime sodium and sulbactam sodium (1:0.5, cefotaxime and sulbactam, respectively) is currently used to treat infectious diseases.
  • One of the clinical first-line drugs One of the clinical first-line drugs.
  • the composite preparation of cefotaxime sodium and sulbactam sodium is difficult to achieve the predetermined ratio in the mixing process due to the large and uneven particle size of the two raw materials after ordinary pulverization.
  • the approved period of use of a drug indicates the period during which the drug is guaranteed to be of a quality under the specified storage conditions.
  • general requirements Purchase of drugs with a validity period of more than one year;
  • the cefotaxime sodium and sulbactam sodium combination preparations are generally valid for 24 months, have a short effective period, and are prone to return and exchange, and are difficult to sell.
  • the compound preparation has uniform particle size, uniform mixing, improved stability, longer shelf life and better quality.
  • Another object of the present invention is to provide a process for the preparation of the cefotaxime sodium and sulbactam sodium combination preparation.
  • cefotaxime sodium and sulbactam sodium compound preparation provided by the invention, the ratio of cefotaxime sodium and sulbactam sodium in the weight fraction of cefotaxime and sulbactam is 1:1.5 ⁇ 0.125; cefotaxime sodium Both sulbactam and sulbactam have a particle size of 2000 to 100,000 nm.
  • the ratio of the cefotaxime sodium and sulbactam sodium in terms of parts by weight of cefotaxime and sulbactam is preferably from 1:1 to 0.5.
  • the particle diameters of the cefotaxime sodium and sulbactam sodium are each preferably from 2000 nm to 75000 nm.
  • nanocarriers refers to various nanoparticles that dissolve or disperse a drug, such as nanoliposomes, polymer nanocapsules, nanospheres, polymer micelles, and the like.
  • Nanomedicine refers to nanoparticles that directly process raw materials into raw materials.
  • the drug of the present invention has a particle size exceeding The above range of nanomedicines has a particle size of more than 2000 nm and thus cannot be called a nanomedicine.
  • the invention has the particle size range of 2000 ⁇ 100000 nm, and the drug particles can be uniformly mixed, the stability is improved, the shelf life is longer, and the quality is better.
  • the particle size is greater than 1000om, the particle mixing is not uniform enough, which may affect the effectiveness and safety of the drug.
  • the particle is less than 2000nm, not only the pulverization cost is greatly improved, such as the conventional micro-nano mechanical pulverization does not meet the requirements, and the gas flow is required.
  • the particle size uniformity can reach the standard, it is highly susceptible to static electricity, which may cause unevenness in the mixing of cefotaxime sodium and sulbactam sodium, and the drug is depleted. Larger, mechanical cleaning after production is difficult.
  • the preparation prepared by the cefotaxime sodium and sulbactam sodium combination preparation of the present invention is an injection form. It is preferably a powder injection.
  • the method for preparing a cefotaxime sodium and sulbactam sodium compound preparation comprises: micronizing cefotaxime sodium and sulbactam sodium respectively, so that the particle size reaches 2000-1000OOm, and then uniformly mixing, that is, obtaining .
  • the preparation method is carried out in a sterile GMP state as a whole.
  • the micronization of the cefotaxime sodium and sulbactam sodium was carried out using a nanopulverizer.
  • the micropulverization using the nanopulverizer is significantly shorter than that of the ordinary mechanical micronization, and the time saving effect is 20 to 200%.
  • the mixing is uniform and is carried out using a V-type high efficiency mixer.
  • the rotation speed of the V-type high-efficiency mixer is: 12 ⁇ 100 r/min, preferably 15 ⁇ 25 r/min.
  • the mixing is uniform, and the mixing time is 15 to 45 minutes, preferably 20 to 30 minutes.
  • the compound preparation is made into a powder injection, after evenly mixing, it also includes filling and filling and glanding under nitrogen filling. Further, the capping operation refers to: press-coated butyl rubber stopper.
  • the method for preparing the cefotaxime sodium and sulbactam sodium compound preparation according to the present invention is characterized in that the cefotaxime sodium and the sulbactam sodium are separately crushed, and the cefotaxime and sulbactam are used in parts by weight. After mixing (1:1.5 ⁇ 0.125), the ratio of cefotaxime sodium to sulbactam sodium can meet the ratio.
  • cefotaxime sodium and sulbactam sodium combination preparations of the present invention have an obvious therapeutic effect especially for NDM-1 resistant bacteria infection.
  • the invention uses the nano-crushing technology to micronize cefotaxime sodium and sulbactam sodium to the nanometer level, effectively shortens the pulverization time, pulverizes the uniform particle size, and makes the ratio of cefotaxime sodium and sulbactam sodium evenly mixed. It can meet the matching requirements and solve the problem of uneven mixing due to different particle size of raw materials, making the product uniform in particle size, stable in ratio, easy to control in quality, easy to store, and resistant to NDM-1 "super bacteria".
  • the drug infection has obvious therapeutic effect; at the same time, the nano-scale cefotaxime sodium and sulbactam sodium preparations are stable at 60 ° C, and the effective period is 28 months, which solves the problem of high temperature stability at 60 ° C. And the short-lived problem, easy to transport and long-term preservation, are superior to the existing technology, improving drug safety and economic benefits.
  • GMP sterile conditions refers to a process of producing aseptic comply with GMP conditions to ensure “sterility assurance level” (Sterility Assurance Level, SAL) is no greater than 10-3, sterile drug directly min
  • SAL Steility Assurance Level
  • Cefotaxime sodium (based on cefotaxime) lg Sulbactam sodium (in terms of sulbactam) 1.5 g
  • Preparation method Under GMP aseptic conditions, cefotaxime sodium and sulbactam sodium were micronized by a nanopulver, respectively, to a particle size of 2000 nm, according to the prescription After the ratio of the composition requirements is calculated, the material is fed, mixed with a V-type high-efficiency mixer at a speed of 17 r/min, and the mixing time is 20 min. The filling and laminating butyl rubber caps are filled under nitrogen. , to obtain the target powder injection.
  • Cefotaxime sodium (based on cefotaxime) lg
  • Preparation method Under GMP aseptic conditions, cefotaxime sodium and sulbactam sodium were respectively micronized by a nano-pulverizer to make the particle size of 5000 nm, and the ratio of the prescription composition was calculated and then charged, and the V-type was used.
  • the high-efficiency mixer was mixed at a speed of 15 r/min, and the mixing time was 30 min.
  • the filling and sub-packing and butyl rubber stopper were filled under nitrogen to obtain the target powder injection.
  • Cefotaxime sodium (based on cefotaxime) lg
  • Preparation method Under GMP aseptic conditions, cefotaxime sodium and sulbactam sodium were micronized by nano-pulverizer respectively, so that the particle size was 1000 nm, and the ratio of the prescription composition was calculated and then charged, and the V-type was used.
  • the high-efficiency mixer was mixed at a speed of 25 r/min, and the mixing time was 25 min.
  • the target powder injection was prepared by filling and laminating the butyl rubber stopper under nitrogen.
  • Cefotaxime sodium (based on cefotaxime) lg Sulbactam sodium (in terms of sulbactam) 0.5g
  • cefotaxime sodium and sulbactam sodium were micronized by a nanopulver, respectively, to a particle size of 75000 nm, according to the prescription
  • the material is fed.
  • the mixture is mixed with a V-type high-efficiency mixer at a speed of 17 r/min.
  • the mixing time is 25 min.
  • the filling and laminating butyl rubber caps are filled under nitrogen. , to obtain the target powder injection.
  • Cefotaxime sodium (based on cefotaxime) lg
  • Preparation method Under GMP aseptic conditions, cefotaxime sodium and sulbactam sodium were micronized by nano-pulverizer respectively, so that the particle size was 50000 nm, and the ratio of the prescription composition was calculated and then charged, and the V-type was used.
  • the high-efficiency mixer was mixed at a speed of 17 r/min, and the mixing time was 25 min.
  • the target powder injection was prepared by filling and laminating the butyl rubber stopper under nitrogen.
  • Cefotaxime sodium (based on cefotaxime) lg
  • Preparation method Under GMP aseptic conditions, cefotaxime sodium and sulbactam sodium were micronized by nano-pulverizer respectively, so that the particle size is 1000OOm, and the ratio is calculated according to the prescription composition, and then the material is fed.
  • the high-efficiency mixer was mixed at a speed of 17 r/min, and the mixing time was 25 min.
  • the target powder injection was prepared by filling and laminating the butyl rubber stopper under nitrogen.
  • Cefotaxime sodium (based on cefotaxime) lg Sulbactam sodium (in terms of sulbactam) 0.125g
  • Preparation method Under GMP aseptic conditions, cefotaxime sodium and sulbactam sodium were micronized by nano-pulverizer to make the particle size of 120,000 nm, according to the prescription. After the proportion of the composition requirements is calculated, the material is fed. The mixture is mixed with a V-type high-efficiency mixer at a speed of 17 r/min. The mixing time is 25 min. The filling and laminating butyl rubber caps are filled under nitrogen. , to obtain the target powder injection.
  • NS-87 Morgan Morganella
  • NS-91 Klebsiella pneumoniae
  • NS-96 Esscherichia coli
  • the strain was first corrected to 0.5 mM turbidity with physiological saline, and then diluted 1:10 with MH broth (containing about 107 CFU/mL), and 50 ul of diluted broth was added to each tube and positive.
  • MH broth containing about 107 CFU/mL
  • 50 ul per tube the final bacterial concentration was 5 X 105 CFU/mL.
  • the tube stopper was placed and placed in a 37 ° C incubator overnight to determine the minimum inhibitory concentration (MIC).
  • Table 1 The results are shown in Table 1:
  • the drug combination of the invention has obvious antibacterial activity against three strains producing NDM-1, especially when cefotaxime sodium/sulbactam sodium (with cefotaxime and When the weight ratio of sulbactam is 1: 1 ⁇ 0.5, the antibacterial effect is the strongest.
  • the error ratio of the mass ratio of cefotaxime sodium to sulbactam sodium is not to exceed 4%.
  • the pharmaceutical composition of the present invention is unevenly mixed after coarse crushing, and does not meet the requirements; after ordinary pulverization, ultrasonic pulverization and nano-pulverization to obtain 120000 nm particles, the mass ratio error is barely in compliance with regulations, but is close to Unqualified limits, multi-volume production is prone to uneven mixing.
  • the particles having a particle diameter ranging from 2000 nm to 1000 ⁇ are uniformly mixed and conform to the regulations, and the mixing uniformity is obviously superior to other cases.
  • the preparation prepared by the cefotaxime sodium sulbactam sodium granule obtained by the treatment of the present invention has a significantly higher high temperature stability than the smear control.
  • Experimental Example 4 Accelerated test to evaluate the effect of particle size on the stability of cefotaxime sodium and sulbactam composite preparations
  • Nano-pulverization of the invention (Examples 1 and 4, particle diameters of 2000 nm and 75000 nm, respectively), common sale (produced by Xiangbei Welman Pharmaceutical Co., Ltd., batch number: 070520), at 25 Placed at °C ⁇ 2 °C, RH 60% ⁇ 10% for 28 months, and samples were taken at the end of the 3rd, 6th, 9th, 12th, 18th, 24th and 28th month of the experiment. The results are shown in Table 5. .
  • the present invention provides a compound preparation which can treat infections of drug-resistant bacteria such as NDM-1 "super bacteria"; although the high temperature test and the accelerated test are still within the scope prescribed by the drug, the ordinary sale product is still qualified. However, the quality of the product is deteriorating. In the long-term experiment, the common sale is unqualified in 28 months and still qualified in the first 24 months. By comparison, the stability of 2000nm ⁇ 100000nm is better and can be stabilized for 28 months.
  • the invention solves the problem of uneven mixing due to uneven particle size of the raw materials, and makes the product quality easy to control; at the same time, the cefotaxime sodium and sulbactam sodium compound preparation can be kept stable at 60 ° C, and the effective period reaches 28 In the month, it solved the problem of high temperature stability at 60 °C and the short period of validity, which is convenient for transportation and long-term preservation, and improves drug safety and economic benefits.
  • cefotaxime sodium and sulbactam sodium preparations of the invention have antibacterial effects, especially for NDM-1 resistant bacteria infection.

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Abstract

本发明涉及一种头孢噻肟钠和舒巴坦钠的复方制剂，以及它的制备方法和应用。所述复方制剂中头孢噻肟钠和舒巴坦钠以头孢噻肟和舒巴坦重量份计的配比为1:1.5～0.125；头孢噻肟钠和舒巴坦钠的粒径均为2000～100000nm。本发明采用纳米粉碎技术，在60℃保持稳定，且有效期达到28个月，解决了高温稳定性问题和有效期较短的问题，便于运输和长时间保存，均优于现有技术，提高了药品安全性和经济效益。

Description

头孢噻肟钠和舒巴坦钠的复方制剂及其制备方法和应用 技术领域
本发明涉及药物复方制剂领域， 具体地， 涉及一种头孢噻肟钠和 舒巴坦钠的复方制剂， 以及它的制备方法和应用。 背景技术
本发明涉及的一种头孢噻肟钠和舒巴坦钠的复方制剂，是一种治 疗产 NDM-1 "超级细菌"等耐药菌感染的活性成分含量稳定的药物组 合物。 NDM-1是新德里金属 β -内酰胺酶 -1 ( New Delhi metallo- β -lactamase- 1 ) 的英文缩写， 由 2010年 8月 11曰发表在英国著名医学杂 志 《The Infectious Diseases》 的一篇文章所报道， 刊登出英国卡迪福 大学的蒂姆.沃尔什将超级细菌命名为 "新德里金属蛋白酶 -1" , 由于 携带该基因的细菌会产生一种特殊的 β -内酰胺酶， 且活性部位为金 属离子又首先在印度首都新德里出现所以得名： NDM-1。 产 NDM-1 的细菌一般以大肠埃希菌和肺炎克雷伯菌为主，这些细菌既可引起医 院内感染， 也有社区感染， 包括尿路感染、 血流感染、 肺炎、 导管相 关感染、 伤口感染等。 全球上巿的近 200种抗生素对这种新型超级细 菌几乎束手无策 （房咪等， "超级细菌" NDM-1的发现及研究进展。 国外医药抗生素分册， 2011 , 32 ( 6 ): 253-8 )。 因此， 寻找一种能有 效抑制产 NDM-1 "超级细菌" 等耐药菌感染的药物已经迫在眉睫。
头孢噻肟钠为第三代头孢类半合成广谱抗菌素，该药具有抗菌谱 广， 抗菌作用强， 毒副作用小等优点。 临床广泛应用于治疗敏感细菌 引起的的败血症、化脓性脑膜炎及呼吸道、 泌尿道、胆道、 骨和关节、 皮肤和软组织、 腹腔、 消化道、 五官、 生殖器等部位的感染， 也可用 于免疫功能低下、 抗体细胞减少等防御功能低下的感染性疾病的治 疗。
头孢噻肟钠在刚开始应用上巿时， 对 β -内酰胺酶较稳定。 但随 着头孢噻肟钠在临床上的广泛应用及超广谱 β -内酰胺酶的出现， 耐 头孢噻肟钠的细菌逐年增多， 尤其是大肠埃希菌、 伤寒沙门菌、 肺炎 克雷伯菌、 普通变形杆菌等产生的超广谱 β -内酰胺酶， 其由质粒介 导， 能有效水解头孢噻肟钠， 给临床治疗感染性疾病带来很大困难。 该耐药基因又可通过不同的转移元件转移到质粒上，使耐药基因在大 范围内传播。 为了控制和解决临床上日益严重的产超广谱 β -内酰胺 酶的细菌感染问题， β -内酰胺酶抑制剂与 β -内酰胺抗生素的复方制 剂得以开发应用。 目前临床上对产超广谱 β -内酰胺酶的细菌引起的 感染， 可选用 β -内酰胺酶抑制剂舒巴坦钠与头孢噻肟钠的复合制剂 (王霆等， 头孢噻肟钠与 β -内酰胺酶抑制剂复方研究进展。 中国新 药杂志， 2010, 19 ( 5 ): 377-85 )。
根据文献报道（钟巍等， 不同配比头孢噻肟和舒巴坦的体外抗菌 作用， 中国临床药理学杂志， 2005 , 21 ( 5 ): 345-50 ), 不同配比的 头孢噻肟和舒巴坦（1 :1、 1:0.5、 1:0.25、 1:0.125 )联合使用可以显著 降低产超广谱 β -内酰胺酶的细菌的耐药性。 头孢噻肟和舒巴坦的配 比为 1: 1和 1:0.5时抗菌活性和杀菌作用最强， 且两种配比的作用相当； 而头孢噻肟和舒巴坦的配比为 1:0.25和 1:0.125时， 抗菌活性和杀菌作 用明显降低。
临床上实际使用的是头孢噻肟和舒巴坦的钠盐，头孢噻肟钠和舒 巴坦钠（1:0.5 , 分别以头孢噻肟和舒巴坦计）复方制剂是目前治疗感 染性疾病的临床一线药物之一。 但是， 头孢噻肟钠和舒巴坦钠的复合 制剂在生产过程中， 由于两种原料的经普通粉碎后粒径较大且不均 匀， 导致在混合过程中很难达到既定的配比要求， 从而导致药品质量 难以控制； 若要使头孢噻肟钠和舒巴坦钠复方制剂符合质量标准， 则 需要长时间粉碎， 但时间粉碎会导致产生较高的温度， 导致产品质量 药品有效期是指该药品被批准的使用期限，表示该药品在规定的 贮存条件下能够保证质量的期限。 在医院的釆购过程中， 一般要求釆 购有效期剩余 1年以上的药品； 在仓储和药房配发过程中， 往往会发 生药品因过期或即将过期而不能配发的情况。头孢噻肟钠和舒巴坦钠 复方制剂的有效期一般为 24个月， 有效期较短， 易发生退换货、 难以 销售等问题。
但是， 头孢噻肟钠和舒巴坦钠复方制剂的粒径不均匀问题、 高温 稳定性、 尤其是 60°C的高温稳定性问题和有效期较短的问题， 至今未 得到解决。 若这些问题均能得到解决， 势必会对头孢噻肟钠和舒巴坦 钠复方制剂领域有很大的贡献。 发明内容
为了解决上述问题， 本发明的目的之一在于， 提供一种头孢噻肟 钠和舒巴坦钠复方制剂。 该复方制剂粒径均匀， 且混合均匀、 稳定性 提高， 保质期更长， 质量更好。
本发明的另一目的在于，提供一种所述头孢噻肟钠和舒巴坦钠复 方制剂的制备方法。
本发明的又一目的在于，提供一种所述头孢噻肟钠和舒巴坦钠复 方制剂在制备治疗抗菌药物中的应用。
本发明提供的头孢噻肟钠和舒巴坦钠复方制剂，头孢噻肟钠和舒 巴坦钠以头孢噻肟和舒巴坦重量份计的配比为 1:1.5 ~ 0.125； 头孢噻 肟钠和舒巴坦钠的粒径均为 2000 ~ 100000nm。
其中，所述头孢噻肟钠和舒巴坦钠以头孢噻肟和舒巴坦重量份计 的配比优选为 1 : 1 ~ 0.5。
其中， 所述头孢噻肟钠和舒巴坦钠的粒径均优选为： 2000nm~75000nm。
药剂学中的纳米粒的尺寸界定在 1 ~ 1000 nm之间，其可以分成两 类： 纳米载体和纳米药物。 纳米载体系指溶解或分散有药物的各种纳 米粒， 如纳米脂质体、 聚合物纳米囊、 纳米球、 聚合物胶束等。 纳米 药物则是指直接将原料药物加工成的纳米粒。本发明的药物粒径超过 上述纳米药物的范围， 粒径为大于 2000 nm, 因而不能称之为纳米药 物。 本发明使粒径范围定在 2000 ~ 100000 nm, 药物颗粒能够混合均 匀、 稳定性提高、 保质期更长， 质量更好。 当粒径大于 lOOOOOnm时 颗粒混合不够均匀， 有可能影响药物的有效性和安全性； 当颗粒小于 2000nm时， 不但粉碎成本大大提高， 如常规的微纳米机械粉碎达不 到要求， 需要釆用气流粉碎机、 超声喷雾器等方法， 此外， 虽然颗粒 粒径的均匀度也可以达到标准， 但极易受静电干扰， 易导致头孢噻肟 钠和舒巴坦钠混合时产生不均匀问题， 而且药物耗损较大， 生产后的 机械清洁困难。
本发明的头孢噻肟钠和舒巴坦钠复方制剂所制得的制剂为注射 剂型。 优选为粉针剂。
本发明提供的制备头孢噻肟钠和舒巴坦钠复方制剂的方法， 包 括： 将头孢噻肟钠和舒巴坦钠分别进行微粉化， 使粒径达到 2000 ~ lOOOOOnm, 再混合均匀， 即得。
上述制备方法中：
其中， 所述制备方法， 整体都是在无菌 GMP状态下进行的。 其中，所述头孢噻肟钠和舒巴坦钠的微粉化是利用纳米粉碎机进 行的。 就使微粉化的粒径合格的时间而言， 使用纳米粉碎机微粉化比 使用普通机械微粉化明显缩短， 节省时间效果达 20~200%。
其中， 所述混合均匀， 是用 V型高效混合机进行的。
其中， 所述 V型高效混合机的转速为： 12~100 r/min, 优选 15~25 r/min„
其中， 所述混合均匀， 混合时间为 15~45min, 优选 20~30 min。 当复方制剂制成粉针剂时， 混合均匀后， 还包括在充氮气下进行 填充分装和压盖。 进一步地， 压盖操作是指： 压复膜丁基胶塞盖。
本发明所述制备头孢噻肟钠和舒巴坦钠复方制剂的方法，是将头 孢噻肟钠和舒巴坦钠分别粉碎后， 以头孢噻肟和舒巴坦的重量份计的 配比 （ 1:1.5 ~ 0.125 ) 混合后， 头孢噻肟钠和舒巴坦钠的比例能够达 到所述配比要求。
本发明的又一目的在于，提供一种所述头孢噻肟钠和舒巴坦钠复 方制剂在制备治疗抗菌药物中的应用。
本发明所述头孢噻肟钠和舒巴坦钠复方制剂尤其对于 NDM-1耐 药菌感染有明显的治疗作用。
本发明釆用纳米粉碎技术，将头孢噻肟钠和舒巴坦钠微粉化至纳 米级， 有效缩短粉碎时间， 粉碎粒径均匀， 并使混合均匀后头孢噻肟 钠和舒巴坦钠的比例能够达到配比要求，解决了由于原料粒径不同导 致的混合不均匀的问题， 使产品粒径均匀、 配比稳定、 质量易控制、 易于保存， 且对产 NDM-1 "超级细菌"等耐药菌感染有明显的治疗作 用； 同时， 纳米级的头孢噻肟钠和舒巴坦钠复方制剂， 在 60°C贮存保 持稳定， 且有效期达到 28个月， 解决了 60°C高温稳定性问题和有效期 较短的问题， 便于运输和长时间保存， 均优于现有技术， 提高了药品 安全性和经济效益。 具体实施方式
以下实施例用于说明本发明， 但不用来限制本发明的范围。
本发明提到的 "GMP无菌条件" 是指符合相关 GMP条件的无菌 生产工艺， 以保证 "无菌保证水平"（Sterility Assurance Level, SAL ) 不大于 10-3 , 无菌原料药直接分装制剂的生产过程应在严格符合相关 GMP条件的无菌条件下进行，同时需要对直接接触药品的包装材料和 容器、 制剂设备等釆用适当的方法灭菌。
本发明所用设备，实施例和实验例中所用物料均可以从巿场上购 买得到。
实施例 1
处方组成：
头孢噻肟钠 （以头孢噻肟计 ) lg 舒巴坦钠 （以舒巴坦计） 1.5g 制备方法： 在 GMP无菌条件下，将头孢噻肟钠和舒巴坦钠分别用 纳米粉碎机微粉化， 使粒径均为 2000nm, 按处方组成要求的比例计 算好后进行投料， 用 V型高效混合机， 转速 17 r/min, 进行混合， 混料 时间为 20 min, 在充氮气下进行填充分装和压复膜丁基胶塞盖， 制得 目标粉针剂。
实施例 2
处方组成：
头孢噻肟钠 （以头孢噻肟计 ) lg
舒巴坦钠 （以舒巴坦计） 1.25g
制备方法： 在 GMP无菌条件下，将头孢噻肟钠和舒巴坦钠分别用 纳米粉碎机微粉化， 使粒径均为 5000nm, 按处方组成要求的比例计 算好后进行投料， 用 V型高效混合机， 转速 15 r/min, 进行混合， 混料 时间为 30 min, 在充氮气下进行填充分装和压复膜丁基胶塞盖， 制得 目标粉针剂。
实施例 3
处方组成：
头孢噻肟钠 （以头孢噻肟计 ) lg
舒巴坦钠 （以舒巴坦计） lg
制备方法： 在 GMP无菌条件下，将头孢噻肟钠和舒巴坦钠分别用 纳米粉碎机微粉化， 使粒径均为 lOOOOnm, 按处方组成要求的比例计 算好后进行投料， 用 V型高效混合机， 转速 25 r/min, 进行混合， 混料 时间为 25 min, 在充氮气下进行填充分装和压复膜丁基胶塞盖， 制得 目标粉针剂。
实施例 4
处方组成：
头孢噻肟钠 （以头孢噻肟计 ) lg 舒巴坦钠 （以舒巴坦计） 0.5g 制备方法： 在 GMP无菌条件下，将头孢噻肟钠和舒巴坦钠分别用 纳米粉碎机微粉化， 使粒径均为 75000nm, 按处方组成要求的比例计 算好后进行投料， 用 V型高效混合机， 转速 17 r/min, 进行混合， 混料 时间为 25 min, 在充氮气下进行填充分装和压复膜丁基胶塞盖， 制得 目标粉针剂。
实施例 5
处方组成：
头孢噻肟钠 （以头孢噻肟计 ) lg
舒巴坦钠 （以舒巴坦计） 0.25g
制备方法： 在 GMP无菌条件下，将头孢噻肟钠和舒巴坦钠分别用 纳米粉碎机微粉化， 使粒径均为 50000nm, 按处方组成要求的比例计 算好后进行投料， 用 V型高效混合机， 转速 17 r/min, 进行混合， 混料 时间为 25 min, 在充氮气下进行填充分装和压复膜丁基胶塞盖， 制得 目标粉针剂。
实施例 6
处方组成：
头孢噻肟钠 （以头孢噻肟计 ) lg
舒巴坦钠 （以舒巴坦计） 0.125g
制备方法： 在 GMP无菌条件下，将头孢噻肟钠和舒巴坦钠分别用 纳米粉碎机微粉化， 使粒径均为 lOOOOOnm, 按处方组成要求的比例 计算好后进行投料， 用 V型高效混合机， 转速 17 r/min, 进行混合， 混 料时间为 25 min, 在充氮气下进行填充分装和压复膜丁基胶塞盖， 制 得目标粉针剂。
对比例
处方组成：
头孢噻肟钠 （以头孢噻肟计 ) lg 舒巴坦钠 （以舒巴坦计） 0.125g 制备方法： 在 GMP无菌条件下，将头孢噻肟钠和舒巴坦钠分别用 纳米粉碎机微粉化， 使粒径均为 120000nm, 按处方组成要求的比例 计算好后进行投料， 用 V型高效混合机， 转速 17 r/min, 进行混合， 混 料时间为 25 min, 在充氮气下进行填充分装和压复膜丁基胶塞盖， 制 得目标粉针剂。
实验例 1 : 不同比例头孢噻肟钠和舒巴坦纳对三株临床分离的产 NDM-1的菌株的抑菌作用
菌株： NS-87 (摩根摩根菌）、 NS-91 (肺炎克雷伯菌）、 NS-96 (大 肠埃希菌）。 这些菌株在巿场上均可以购买得到。
方法： 将不同比例的 （实施例 1~6 ) 头孢噻肟钠和舒巴坦钠复合 制剂用蒸馏水稀释至 512mg/L。 每测定一种样品时均取 15支试管， 另 取 2支分别做阳性对照和阴性对照。各试管均加 lmL MH肉汤。将 lmL 用蒸馏水稀释至 512mg/L的样品加入第一支试管， 混匀后吸出 lmL至 第 2支试管， 依次 2倍稀释至第 15支试管， 吸出 lmL弃去。 此时， 各管 样品浓度分别为 256、 128、 64、 32、 16、 8、 4、 2、 1、 0.5、 0.25、 0.125、 0.06、 0.03、 0.015mg/L。 菌株先用生理盐水校正至 0.5麦氏比浊浓度， 再用 MH肉汤 1: 10稀释（含菌量约为 107 CFU/mL ), 将 50ul稀释后的 菌液分别从加至各管和阳性对照管， 每管 50ul, 最终菌液浓度为 5 X 105 CFU/mL。 接种后盖上试管塞， 放入 37°C恒温培养箱过夜后测定 最低抑菌浓度（MIC ), 结果如表 1所示：
表 1 : 不同比例头孢噻肟钠和舒巴坦钠复合制剂 对三株临床分离的产 NDM-1的菌株的抑菌作用
Figure imgf000009_0001
1 : 0.25 0.5 0.06 0.06
>256 >256 256 表 1 O结果可见： 本发明药物组合对三株产 NDM-1的菌株有明显的 抑菌作用， 特别是当头孢噻肟钠 /舒巴坦钠 （分别以头孢噻肟和舒巴 坦计） 的重量配比为 1 : 1 ~ 0.5时， 抑菌作用最强。
实验例 2: 头孢噻肟钠舒巴坦纳的粒径对混合均匀程度的影响
方法： 将粗碎（粒径 4mm )、 普通粉碎（粒径 500um )、 超声粉碎 (粒径 1000 nm ) 和本发明的纳米粉碎 （粒径 2000 nm、 75000 nm 100000 nm )及对比例的纳米粉碎 ( 120000匪 ), 分别为实施例 1、 实 施例 4、 实施例 6和对比例得到的头孢噻肟钠和舒巴坦钠复合制剂。 取 样进行含量测定， 结果如表 2所示：
表 2: 粒径对混合均匀程度的影响
Figure imgf000010_0001
本发明的药物组合物的质量标准中，规定头孢噻肟钠和舒巴坦钠 质量比例误差不得超过 4%。 根据表 2结果可见， 本发明的药物组合物 经粗碎后混合不均匀， 不符合规定； 经普通粉碎、 超声粉碎及纳米粉 碎得到 120000 nm颗粒后， 质量比例误差虽然勉强符合规定， 但已经 接近不合格的限度， 多批量生产极易出现混合度不均匀的情况。 本发 明中粒径为 2000nm至 lOOOOOnm范围的颗粒， 混合均匀， 符合规定， 且混合均匀程度明显优于其他几种情况。
实验例 3: 高温试验评价粒径对头孢噻肟纳和舒巴坦纳复合制剂稳定 性的影响
方法： 分别取三批样品： 本发明的纳米粉碎（实施例 1和 4, 粒径 分别为 2000nm和 75000nm ), 普通巿售品 （湘北威尔曼制药有限公司 生产， 批号： 070520 ), 在 60°C条件下放置 10天， 并于实验的第 5、 10 天取样实验， 结果如表 3所示。
表 3: 高温试验评价粒径对头孢噻肟钠和舒巴坦钠复合制剂稳定性的影响
从上表可以看出： 以经过本发明处理获得的头孢噻肟钠舒巴坦钠 颗粒制备的制剂的高温稳定性明显优于巿售对照品。 实验例 4: 加速试验评价粒径对头孢噻肟钠和舒巴坦纳复合制剂稳定 性的影响
方法： 分别取三批样品： 本发明的纳米粉碎（实施例 1和 4, 粒径 分别为 2000nm和 75000nm ), 普通巿售品 （湘北威尔曼制药有限公司 生产， 批号： 070520 ), 在 40°C ± 2°C、 RH 75 % ± 5 %的条件下放置 6 个月， 并于实验的第 1、 2、 3、 6月末取样实验， 结果如表 4所示。 表 4: 加速试验评价粒径对头孢噻肟钠和舒巴坦钠复合制剂稳定性的影响
Figure imgf000012_0001
pH值 4.0 - 6.5 4.9 4.9 4.9 5.0 5.1 从上表可以看出： 以经过本发明处理获得的头孢噻肟钠舒巴坦钠 颗粒制备的制剂的加速稳定性明显优于巿售对照品。
实验例 5: 长期试验评价粒径对头孢噻肟钠和舒巴坦纳复合制剂稳定 性的影响
方法： 分别取三批样品： 本发明的纳米粉碎（实施例 1和 4, 粒径 分别为 2000nm和 75000nm ), 普通巿售品 （湘北威尔曼制药有限公司 生产， 批号： 070520 ), 在 25 °C ± 2°C、 RH 60 % ± 10 %的条件下放置 28个月， 并于实验的第 3、 6、 9、 12、 18、 24、 28个月末取样实验， 结果如表 5所示。
表 5: 长期试验评价粒径对头孢噻肟钠和舒巴坦钠复合制剂稳定性的影响
Figure imgf000013_0001
舒巴坦钠 标示量
98.5% 97.9% 96.1% 95.6% 92.6% 90.5% 88.1% 含量 （ ) 90%-110%
不符 溶液澄明 应符合 符合 符合 符合 符合 符合 符合 符合
合 度与颜色 规定 规定 规定 规定 规定 规定 规定 规定
规定 有关物质 不超过 5% 1.14% 1.35% 1.51% 2.13% 2.64% 3.07% 4.51% 4.93% 聚合物 不超过 1% 0.12% 0.28% 0.44% 0.53% 0.64% 0.75% 0.92% 1.27% pH值 4.0 ~ 6.5 4.9 4.9 4.9 4.9 4.9 5.0 5.2 5.4 从上表可以看出： 以经过本发明处理获得的头孢噻肟钠舒巴坦钠 颗粒制备的制剂的长期稳定 bo性明显优于巿售对照品，而且放置 28个月 仍然符合本品的质量标准， 其有效期至少可以长达 28个月。
表 3~5结果可见， 本发明复合制剂中的头孢噻肟钠和舒巴坦钠粒 径均达到纳米级时， 稳定性优于普通巿售品。 本发明的复合制剂在高 温试验、 加速试验和长期试验中均稳定， 能在 60°C保持稳定， 有效期 达到 28个月，而头孢噻肟钠舒和巴坦钠的普通巿售品在 28个月的长期 实验中不稳定。 稳定性考察粒径范围为 2000~75000 nm时效果较优， 结合混合均匀度得到了 2000-100000 nm的范围。
由此可见， 本发明提供了一种可以治疗产 NDM-1 "超级细菌"等 耐药菌感染的复方制剂；虽然高温试验和加速实验由于在药品规定的 范围内， 普通巿售品仍然合格， 但是产品质量下降的比较厉害； 在长 期实验中， 普通巿售品在 28个月不合格， 前 24个月仍然合格； 通过比 较， 2000nm~100000nm的稳定性更好， 能稳定 28个月。 即本发明解决 了由于原料粒径不均匀导致的混合不均匀的问题， 使产品质量易控 制； 同时可使头孢噻肟钠和舒巴坦钠复方制剂在 60°C保持稳定， 且有 效期达到 28个月， 解决了 60°C高温稳定性问题和有效期较短的问题， 便于运输和长时间保存， 提高药品安全性和经济效益。 工业实用性
本发明所述头孢噻肟钠和舒巴坦钠复方制剂具有抗菌作用，尤其 对于 NDM-1耐药菌感染有明显的治疗作用。

Claims

权 利 要 求 书
1、 一种头孢噻肟钠和舒巴坦钠复方制剂， 其特征在于， 头孢噻 肟钠和舒巴坦钠以头孢噻肟和舒巴坦重量份计的配比为 1:1.5 ~ 0.125; 头孢噻肟钠和舒巴坦钠的粒径均为 2000 ~ 100000nm。
2、 根据权利要求 1所述的复方制剂， 其特征在于， 所述头孢噻 肟钠和舒巴坦钠以头孢噻肟和舒巴坦重量份计的配比为 1 : 1 ~ 0.5。
3、 根据权利要求 1或 2所述的复方制剂， 其特征在于， 所述头 孢噻肟钠和舒巴坦钠的粒径均为： 2000nm~75000nm。
4、 根据权利要求 1~3任意一项所述的复方制剂， 其特征在于， 所述复方制剂为注射剂型。
5、 根据权利要求 4所述的复方制剂， 其特征在于， 所述复方制 剂为粉针剂。
6、 制备权利要求 1~5任意一项所述的复方制剂的方法， 其特征 在于， 包括： 将头孢噻肟钠和舒巴坦钠分别进行微粉化， 使粒径达到 2000 ~ lOOOOOnm, 再混合均匀， 即得。
7、 根据权利要求 6所述的制备方法， 其特征在于， 所述头孢噻 肟钠和舒巴坦钠的微粉化是利用纳米粉碎机进行的。
8、 根据权利要求 6或 7所述的制备方法， 其特征在于， 所述混 合均匀， 是用 V型高效混合机进行的， 其转速为： 12~100 r/min。
9、 根据权利要求 8所述的制备方法， 其特征在于， 混合时间为 15~45min。
10、权利要求 1~5任意一项所述的复方制剂在制备治疗抗菌药物 中的应用。
PCT/CN2012/077443 2012-06-25 2012-06-25 头孢噻肟钠和舒巴坦钠的复方制剂及其制备方法和应用 WO2014000144A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101592636A (zh) * 2008-05-28 2009-12-02 广州威尔曼新药开发中心有限公司 一种新的复方头孢噻肟钠舒巴坦钠的检测方法
CN101648016A (zh) * 2008-08-11 2010-02-17 广州威尔曼新药开发中心有限公司 稳定性高的药物组合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101592636A (zh) * 2008-05-28 2009-12-02 广州威尔曼新药开发中心有限公司 一种新的复方头孢噻肟钠舒巴坦钠的检测方法
CN101648016A (zh) * 2008-08-11 2010-02-17 广州威尔曼新药开发中心有限公司 稳定性高的药物组合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WAMG, TING ET AL.: "Compound preparations containing cefotaxime and lactamase inhibitors .", CHINESE JOURNAL OF NEW DRUGS., vol. 19, no. 5, May 2010 (2010-05-01), pages 377 - 385 *

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