WO2013044789A1 - 一种低杂质含量的卡泊芬净制剂及其制备方法和用途 - Google Patents

一种低杂质含量的卡泊芬净制剂及其制备方法和用途 Download PDF

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WO2013044789A1
WO2013044789A1 PCT/CN2012/081956 CN2012081956W WO2013044789A1 WO 2013044789 A1 WO2013044789 A1 WO 2013044789A1 CN 2012081956 W CN2012081956 W CN 2012081956W WO 2013044789 A1 WO2013044789 A1 WO 2013044789A1
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Prior art keywords
pharmaceutical composition
formula
amino acid
temperature
compound
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PCT/CN2012/081956
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English (en)
French (fr)
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洪云海
薛颖
沙丽新
季晓铭
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上海天伟生物制药有限公司
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Application filed by 上海天伟生物制药有限公司 filed Critical 上海天伟生物制药有限公司
Priority to ES201490033A priority Critical patent/ES2495615B1/es
Priority to US14/346,275 priority patent/US9149435B2/en
Priority to DE112012003995.5T priority patent/DE112012003995T5/de
Priority to KR1020147011190A priority patent/KR101720396B1/ko
Priority to IN892KON2014 priority patent/IN2014KN00892A/en
Publication of WO2013044789A1 publication Critical patent/WO2013044789A1/zh

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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid

Definitions

  • the present invention relates to a pharmaceutical composition for the treatment and/or prevention of fungal infections, and to a process for the preparation of the pharmaceutical composition. Background technique
  • Caspofungin is the first product of the echinocandin antifungal, and its structure is as in Formula I.
  • caspofungin The earliest development of caspofungin was in the United States, Merck, which was administered in the form of diacetate, which was marketed under the trade name "Cancidas".
  • the stability of caspofungin is very poor, it is easily degraded to produce impurities, and the degradation impurities of formula II are the main degradation impurities.
  • L-747969 in the registration standard for imported drugs (standard number: JX20050258) for caspofungin acetate for injection. , The relative retention time is RRT1.67.
  • L-747969 is a ring-opening polypeptide compound.
  • composition is more stable due to the inclusion of one or more non-reducing sugars having a glass transition temperature higher than 90 ° C, and an acetate buffer system of pH 5-7, and the stability is significantly better than US5952300.
  • this reference also does not disclose the definition and limitation of caspofungin's formula I I degradation impurities and degradation impurities RRT1.
  • Chinese patent CN102166186A discloses another more stable caspofungin injection formulation composition which provides better stability performance by containing a mixture of sorbitol or sorbitol and other excipients.
  • the formulation has been tested in the course of our formulation and it has been found that the stability of the composition is not satisfactory and its stability is significantly worse than the formulation disclosed in this patent.
  • the reference US20090324635 discloses a caspofungin free of impurities A (Formula II), and a process for preparing such caspofungin.
  • Patent US20090291996 discloses an impurity free C. Caspofungin (formula IV), and a process for preparing such caspofungin and a pharmaceutical composition thereof. These two patents also do not describe and analyze the deuterated degradation impurities of caspofungin and the degradation impurities of RRT 1.35, and they are for the drug substance.
  • No. US20090170753 discloses another stable caspofungin pharmaceutical composition containing an additional amount of a pH adjusting agent of less than 0.3 molar equivalent of caspofungin and an effective form of a lyophilized cake.
  • a pharmaceutically acceptable amount of an excipient which is believed to have better stability due to the inclusion of an additional minor amount of acetate pH adjusting agent. It was measured for the degradation impurity CAF-42, and it was analyzed that the impurity should be an impurity represented by Formula II. The amount of the impurity disclosed is 0. 27%, the stability at 25 ° C, the impurity is significantly increased, the stability at 2-8 ° C, the impurity is not increased, In particular, the formulation 4 has dropped significantly and is counterintuitive, and its data credibility is debatable. Impurities in the active pharmaceutical ingredient, such as impurities in caspofungin, are undesirable, and these impurities may even pose a safety hazard to the patient. However, it is unrealistic to completely remove these impurities, and therefore, reducing the limits of these impurities is a key concern of drug formulation developers.
  • the various pharmaceutical compositions which have been disclosed are not the most desirable formulations, and they have not been effectively and strictly controlled for the main degrading impurities of caspofungin, and the stability thereof has yet to be further improved. Therefore, it is necessary to develop a new pharmaceutical composition and preparation process, which can effectively reduce the main degradation impurities of caspofungin, improve its safety and stability, and prolong the shelf life of the drug.
  • the present inventors conducted a large number of tests in the early stage, and made great progress in the stability of the caspofungin pharmaceutical composition.
  • the present invention provides a low-impurity, safe, stable, reproducible lyophilized pharmaceutical composition, and a process for its preparation, which can be directly used for the treatment/prevention of fungal infections. Summary of the invention
  • the present invention provides an HPLC content of the impurity of formula II in the composition of not more than 0.25%;
  • the HPLC content of the impurity of the formula I I in the composition does not exceed 0.20%
  • the pharmaceutically acceptable salt of the compound of Formula I is an acid addition salt or other form of a salt of an organic acid.
  • the pharmaceutical composition is a lyophilized formulation.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the composition comprises a saccharide protecting agent and an amino acid.
  • the saccharide protecting agent is one or more of sucrose, trehalose, and mannitol.
  • the saccharide protectant is sucrose.
  • the amino acid is a neutral amino acid.
  • the neutral amino acid is selected from one or more of the group consisting of glycine, alanine, serine, tryptophan, tyrosine, and threonine.
  • the neutral amino acid is glycine.
  • the weight ratio of the saccharide protecting agent to the compound of formula I or a pharmaceutically acceptable salt thereof is from 60:1 to 2:1.
  • the weight ratio of the saccharide protecting agent to the compound of formula I or a pharmaceutically acceptable salt thereof is from 20:1 to 4:1.
  • the weight ratio of the amino acid to the compound of formula I or a pharmaceutically acceptable salt thereof is from 1:8 to 4:1.
  • the amino acid is a compound of Formula I or pharmaceutically acceptable thereof
  • the weight ratio of the salt is 1:4 to 1.5:1.
  • the present invention also provides a method of preparing a pharmaceutical composition comprising a saccharide protecting agent and an amino acid, comprising the steps of:
  • step b filtering the solution obtained in step b and filling it into a vial at low temperature
  • the saccharide protectant is sucrose.
  • the amino acid is a neutral amino acid.
  • the neutral amino acid is selected from one or more of the group consisting of glycine, alanine, serine, tryptophan, tyrosine, and threonine.
  • the neutral amino acid is glycine.
  • the weight ratio of the saccharide protecting agent to the compound of formula I is
  • the weight ratio of the saccharide protecting agent to the compound of formula I is from 20:1 to 4:1.
  • the weight ratio of the amino acid to the compound of formula I is from 1:8 to 4:1. In a further embodiment, the weight ratio of the amino acid to the compound of Formula I is
  • the lyophilization process in step d is that after the pre-freezing and one-drying phase of the composition, the temperature in the second drying stage is maintained at 30 ° C -40 ° C, and the maintenance time is 5-20 Hours, the total freeze-dry period does not exceed 52 hours.
  • the temperature of the secondary drying stage is maintained at 35 ° C for a period of 5-16 hours and the total freeze-dry period is no more than 38 hours.
  • step d the lyophilization process described in step d is:
  • the shelf temperature is continuously or intermittently reduced to -45 ⁇ - 40 °C at a rate of 0.1 ⁇ l °C/min; b, the shelf temperature is maintained at -45 ⁇ - 40 °C for 120 ⁇ 180min;
  • the degree of vacuum is turned on, and the degree of vacuum is reduced to below 160 mTor; e, the shelf temperature is continuously or intermittently increased to -30 ⁇ -10 °C at a rate of 0.1 ⁇ 1 °C/min; f, the shelf temperature is between -30 ⁇ -10 °C at single and multiple temperatures Maintain 960-1620min; g, shelf temperature rises to 30-40 °C at a rate of 0.04- l ° C / min; and
  • step d the lyophilization process described in step d is:
  • the shelf temperature is reduced to -40 ° C at a rate of l ° C / min;
  • the shelf temperature is maintained at -40 ° C for 120 min;
  • the degree of vacuum is turned on, and the degree of vacuum is reduced to below 80 mTor;
  • the shelf temperature is raised to -20 ° C at a rate of 0.1 ° C / min;
  • the shelf temperature is maintained at -20 ° C for 540-840 min;
  • the shelf temperature is raised to -10 ° C at a rate of 0.1 ° C / min;
  • the shelf temperature is maintained at -10 ° C for 420-780 min;
  • the shelf temperature is increased to 30-40 ° C at a rate of 0.04-0. l ° C / min;
  • the shelf temperature is maintained at 30-40 ° C for 300-960 min.
  • step d Or the lyophilization process described in step d is:
  • the shelf temperature is reduced to -5 ° C at a rate of l ° C / min;
  • the shelf temperature is maintained at -5 ° C for 30 min;
  • the shelf temperature is reduced to -45 ° C at a rate of l ° C / min;
  • the shelf temperature is maintained at -45 ° C for 150 min;
  • the degree of vacuum is turned on, and the degree of vacuum is reduced to below 160 mTor;
  • the shelf temperature is raised to -30 ° C at a rate of 0.1 ° C / min;
  • the shelf temperature is maintained at -30 ° C for 960 min;
  • the shelf temperature is raised to 35 ° C at a rate of l ° C / min;
  • the shelf temperature is maintained at 35 ° C for 300 min;
  • the shelf temperature is maintained at 35 ° C for 300 min;
  • the present invention also provides the use of any of the above pharmaceutical compositions for the preparation of a medicament for preventing and/or treating a fungal infection in a mammal.
  • Figure 1 is an HPLC chromatogram of Cancidas 1571 in Comparative Example 1.
  • Figure 2 is an HPLC chromatogram of Formulation 3 in the Example at 25 °C for 24 weeks.
  • Figure 3 is an HPLC chromatogram of Formulation 3 in the Example at 24 °C at 2-8 °C.
  • the present inventors have tried different excipients in the study of the chemical stability of the echinocandin antifungal compound caspofungin, and the content of the excipients and the composition containing caspofungin
  • the relationship between the stability has been studied, and it has surprisingly been found that the pharmaceutical composition comprising caspofungin or a pharmaceutically acceptable salt thereof and a saccharide protecting agent and an amino acid is surprisingly stable and stable. Even better than the various compositions of the substance which have been reported, the content of the degradation impurities can be effectively controlled. On the basis of this, the present invention has been completed.
  • pre-freezing refers to the process of fully curing moisture in a liquid product for sublimation under vacuum.
  • One-time drying refers to the process of sublimating solid ice into water vapor by heating the product to remove free water between the solute, which can remove about 90% of the water.
  • Synd drying also known as desorption drying, means that when most of the frozen ice in the product is sublimated, the heating temperature is continuously increased, and part of the combined water inside the product is removed to make the product moisture reach the required process. The temperature rise during this process High is conducive to improving work efficiency.
  • the temperature of the secondary drying stage of the commonly used freeze-drying method is maintained at a low level, such as 25 ° C, or even 15 ° C, resulting in a total freeze-drying cycle.
  • the lyophilization method disclosed in the present invention breaks through the conventional method, adopts a higher secondary drying temperature, and adopts a certain heating rate, which not only reduces the generation of impurities, but also improves the working efficiency.
  • the pharmaceutical composition provided by the invention and the preparation method thereof can better avoid the degradation of caspofungin and can better provide the stability of the pharmaceutical composition.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I and/or a pharmaceutically acceptable salt thereof, wherein the HPLC content of the impurity of formula II in the composition is not more than 0.25%; preferably not more than 0.20%; Excellent does not exceed 0.15%.
  • the HPLC relative retention time (RRT) of the impurity of formula II in the composition of the present invention is 1.64-
  • the pharmaceutical composition provided by the present invention comprises:
  • the saccharide protecting agent is selected from one or more of sucrose, trehalose, and mannitol, preferably sucrose.
  • the amino acid is preferably a neutral amino acid, more preferably one or more of the following: glycine, alanine, serine, tryptophan, tyrosine and threonine; most preferred is glycine.
  • composition of the present invention preferably comprises a weight ratio of the saccharide protecting agent to caspofungin or a pharmaceutically acceptable salt thereof of from 60:1 to 2:1; more preferably a saccharide protecting agent and caspofungin or a pharmaceutically thereof thereof
  • the weight ratio of the acceptable salt is from 20:1 to 4:1.
  • composition of the present invention preferably comprises a weight ratio of amino acid to caspofungin or a pharmaceutically acceptable salt thereof of from 1:8 to 4:1; more preferably an amino acid with caspofungin or a pharmaceutically acceptable salt thereof The weight ratio is 1:4- 1 ⁇ 5: 1.
  • the pharmaceutical compositions provided herein may also contain additional pH adjusting agents such as phosphate buffers, acetate buffers, citrate buffers and the like as pharmaceutically acceptable pH adjusting agents.
  • the pH of the buffer is preferably in the range of 5-7, more preferably 5.5-6.5.
  • the pharmaceutical composition provided by the present invention is a lyophilized powder obtainable by lyophilization.
  • the lyophilized powder can be reconstituted into a liquid composition for parenteral, preferably intravenous, administration with an aqueous solution.
  • the aqueous solution is preferably sterile water for injection, optionally containing methylparaben and/or propylparaben and/or 0.9% benzyl alcohol for bacteriostatic water, or saline (normal sal ine) Or physiological saline (phys iologi cal sal ine), such as 0.9% sodium chloride solution, or 0.45% or 0.225% sodium chloride solution, or Ringer's solution, and / or Ringer lactate Solution.
  • the invention further provides a composition of the invention for the preparation of a fungal infection or condition for the prevention and/or treatment of a mammal, preferably a Candida species and/or a Aspergillus species and/or a Pneumocystis carinii. Use in medicines, preferably intravenous drugs.
  • compositions of the present invention may further comprise, for example, one or more pharmaceutically acceptable excipients, including diluents or carriers well known in the art, which are suitable for compositions intended for parenteral administration.
  • injectable pharmaceutical compositions such as for intramuscular, subcutaneous, intravenous, intraperitoneal or intramuscular administration.
  • excipients may include, for example, antioxidants, skin extenders, preservatives, carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. .
  • Suitable solvents or diluents include, but are not limited to, aqueous solvents, preferably bacteriostatic water for injection comprising methylparaben and/or propylparaben and/or 0.9% benzyl alcohol, or physiological saline ( Normal sal ine) or physiological saline (physical physic sal ine), such as 0.9% gasification pin solution, or 0.45% or 0.25% sodium chloride solution, or Ringer's solution, and / or Ringer Lactate solution.
  • physiological saline Normal sal ine
  • physiological saline physical physic sal ine
  • These solvents and/or diluents can also be used to redissolve the compositions of the invention in lyophilized powder form and/or to further dilute the redissolution solution thus obtained.
  • caspofungin means caspofungin free base.
  • pharmaceutically acceptable salts of caspofungin are described in EP0620232.
  • the invention also includes solvates and/or hydrates thereof.
  • pharmaceutically acceptable salt of caspofungin means a non-toxic salt of caspofungin, preferably a pharmaceutically acceptable salt of caspofungin is an acid addition salt with an organic acid,
  • the organic acid is selected from the group consisting of acetic acid, citric acid, tartaric acid, propionic acid, oxalic acid, malic acid, maleic acid, lactic acid, and glutamic acid.
  • the pharmaceutically acceptable salt of caspofungin is caspofungin diacetate.
  • neutral amino acid refers to the number equal to the basic molecule "-NH 2" with acidic "-C00H” a class of amino acids.
  • the present invention also provides a method of preparing a caspofungin pharmaceutical composition having an impurity content of the formula II of not more than 0.25% (HPLC content), comprising the steps of: a. dissolving the saccharide protecting agent and amino acid in pre-cooled water or a suitable buffer solution; b. adding the compound of formula I to dissolve it;
  • c filtration step b obtained solution and lyophilized in a vial at low temperature
  • the temperature in the secondary drying stage is maintained at 30 ° C -40 ° C, and the maintenance time is 5-20 hours, and the total freeze-drying period does not exceed 52 hours.
  • the temperature in the secondary drying stage is maintained at 35 ° C for a period of 5-16 hours and the total freeze-dry period is no more than 38 hours.
  • the caspofungin pharmaceutical composition Since the caspofungin pharmaceutical composition is sensitive to moisture, the composition must be sufficiently dried. Since caspofungin is extremely unstable at normal temperature and high temperature, and the stability of the currently disclosed caspofungin pharmaceutical composition at room temperature and high temperature is also not satisfactory, the existing caspofungin medicinal preparation
  • the conventional freeze-drying method of the composition wherein the temperature of the secondary drying stage is generally maintained at a lower temperature, as disclosed in US Patent No. 2010137197, the secondary drying stage maintains a temperature of 15 ° C, the highest secondary drying stage. The temperature is maintained at only 25 ° C, which results in low drying efficiency. In order to obtain a lower moisture end product, the total freeze-drying cycle must be long and unfavorable, which is not conducive to actual production.
  • the inventors have found out through a large number of experiments that the pharmaceutical composition provided by the present invention has good stability at high temperature, and the freeze-drying method can be carried out at a higher secondary drying stage temperature, so that time is not only time-consuming. It is shorter and provides superior stability to the composition.
  • the caspofungin pharmaceutical composition of the present invention is stable at room temperature compared to the prior art, which facilitates its storage and transportation;
  • the caspofungin pharmaceutical composition of the present invention can be lyophilized at a relatively high temperature, thereby accelerating the lyophilization process and facilitating actual production.
  • Detection wavelength 220nm
  • Mobile phase A: 0.1% perchloric acid (analytical grade, Shanghai Jinlu Chemical Co., Ltd.) and 0.075% sodium chloride (analytical grade, Sinopharm Chemical Reagent Co., Ltd.) solution (take perchloric acid 1.0ml and chlorine) Sodium hydride 0.75g, dissolved in water and diluted to 1000ml);
  • the flow rate is: lml/min or 1.45ml/min.
  • the retention time of the main peak is about 20 min, which is the same as the patent US2010/0137197 and the like, so the RRT value is a value at a flow rate of 1.45 ml/min.
  • the % relative peak area that is, the HPLC content, is the percentage of the peak area of the peak as a percentage of the total peak area. Comparative example 1
  • the materials used in the following comparative examples and examples were all produced by Shanghai Tianwei Bio-Pharmaceutical Co., Ltd.
  • the preparation of the composition was carried out in accordance with Example 1 of US 2010/0137197. Take 1.20g of trehalose dissolved in 3ml of water, then add 7.5 ⁇ l of glacial acetic acid, adjust to ⁇ 5.1 with 1M sodium hydroxide, then add 0.223g of caspofungin acetate, dissolved gently, and adjusted to pH6.0 with 1M sodium hydroxide, and added to 5mL, 0.22 ⁇ membrane filtration.
  • the composition of the composition before lyophilization (Formulation 1) is as follows: : caspofungin acetate (according to caspofungin base, the same below) 40mg/ml
  • Glacial acetic acid 1.5mg/ml
  • freeze-drying procedure F freeze-drying procedure
  • the shelf temperature is reduced to -40 ° C at a rate of 0.2 ° C / min;
  • the shelf temperature is maintained at -40 ° C for 120 min;
  • the degree of vacuum is turned on, and the degree of vacuum is reduced to below 80 mTor;
  • the shelf temperature is raised to -20 ° C at a rate of 0. rC / min;
  • the shelf temperature is maintained at -20 ° C for 3000 min;
  • the shelf temperature is raised to -15 ° C at a rate of 0. rC / min;
  • the shelf temperature is maintained at -15 ° C for 900 min;
  • the shelf temperature is raised to -10 ° C at a rate of 0. rC / min;
  • the shelf temperature is maintained at -10 ° C for 400 min;
  • the shelf temperature is raised to -5 ° C at a rate of 0. rC / min;
  • the shelf temperature is maintained at -5 ° C for 400 min;
  • the shelf temperature is raised to 15 ° C at a rate of 0. rC / min;
  • the shelf temperature is maintained at 15 ° C for 720min;
  • the shelf temperature rises to 25 ° C at rC / min;
  • the shelf temperature is maintained at 25 ° C for 240 min;
  • Mannitol 20mg/ml Filled into vials in a volume of 1.25ml/bottle and lyophilized (freeze-drying procedure with formula 1, only in the last 15
  • the freeze-drying is stopped and the temperature is no longer raised to 25 °C.
  • Example 1 The freeze-dried products were placed at 40 ° C for stability investigation, and samples were taken for HPLC analysis at 8 and 24 weeks, respectively, and stability studies were carried out at 25 ° C, 65% RH and 2-8 ° C, respectively. And samples were taken for HPLC analysis after 24 weeks (including data at time 0).
  • Example 1 The freeze-dried products were placed at 40 ° C for stability investigation, and samples were taken for HPLC analysis at 8 and 24 weeks, respectively, and stability studies were carried out at 25 ° C, 65% RH and 2-8 ° C, respectively. And samples were taken for HPLC analysis after 24 weeks (including data at time 0).
  • the preparation process is as follows: firstly dissolving the saccharide protecting agent and the amino acid in water or dissolving in the solution containing the optional pH adjuster, and then adding the compound of the formula I or a pharmaceutically acceptable salt thereof to dissolve it, to a certain volume. Volume, followed by lyophilization of the previously obtained solution.
  • composition of each formulation of the composition before lyophilization is as follows:
  • the shelf temperature is reduced to -40 ° C at a rate of rC / min; b, the shelf temperature is maintained at -40 ° C for 120 min;
  • the shelf temperature is raised to -10 ° C at a rate of 0. rC / min; h, the shelf temperature is maintained at -10 ° C for 420 min;
  • the shelf temperature is raised to 35 °C at a rate of 0. rC/min; j, the shelf temperature is maintained at 35 ° C for 960 min;
  • the shelf temperature is reduced to -40 ° C at a rate of rC / min; b, the shelf temperature is maintained at -40 ° C for 120 min;
  • the shelf temperature is raised to -10 ° C at a rate of 0. rC / min; h, the shelf temperature is maintained at -10 ° C for 420 min;
  • the shelf temperature is raised to 35 °C at a rate of 0.04 ° C / min; j, the shelf temperature is maintained at 35 ° C for 300 min;
  • the shelf temperature is reduced to -40 ° C at a rate of 0. rC / min; b, the shelf temperature is maintained at -40 ° C for 120 min;
  • the shelf temperature is raised to -10 ° C at a rate of 0. rC / min; h, the shelf temperature is maintained at -10 ° C for 780 min;
  • the shelf temperature is raised to 30 °C at a rate of 0. rC/min; j, the shelf temperature is maintained at 30 ° C for 600 min;
  • the shelf temperature is reduced to -40 ° C at a rate of rC / min; b, the shelf temperature is maintained at -40 ° C for 120 min;
  • the shelf temperature is raised to -10 ° C at a rate of 0. rC / min; h, the shelf temperature is maintained at -10 ° C for 660 min;
  • the shelf temperature is raised to 40 °C at a rate of 0. rC/min; j, the shelf temperature is maintained at 40 ° C for 600 min;
  • the shelf temperature is reduced to -5 ° C at a rate of rC / min; b, the shelf temperature is maintained at -5 ° C for 30 min;
  • the shelf temperature is reduced to -45 ° C at a rate of rC / min; d, the shelf temperature is maintained at -45 ° C for 150 min;
  • the temperature of the cold trap drops below -45 ° C; f, the degree of vacuum is turned on, the vacuum is reduced to less than 160 mTor; g, the shelf temperature is raised to -30 ° C at a rate of 0. rC / min; h, the shelf temperature is maintained at -30 ° C for 960 min; The shelf temperature rose to 35 ° C at rC /min;
  • the shelf temperature is maintained at 35 ° C for 300 min;
  • the vacuum is reduced to below 20mTor
  • the shelf temperature is maintained at 35 ° C for 300 min;
  • Example 2 After the drying is completed, the plug is pressed out, the box is taken out, and the lid is rolled. After each formulation was lyophilized, the stability study described in Comparative Example 2 was also carried out. Example 2
  • Example 3 The sodium hydroxide was adjusted to ⁇ 6 ⁇ 0.
  • the lyophilized products were placed at 40 ° C for stability investigation, and samples were taken for HPLC analysis at 8 and 24 weeks, respectively, and at 25 ° C, 65% RH and 2-8 °, respectively. Stability was examined under C conditions and samples were taken for HPLC analysis after 24 weeks (including data at time 0).
  • Comparative Examples 2, 3 and 4 and Example 1 were examined for stability, respectively, and the samples were analyzed by HPLC.
  • the sucrose glycine formula is the most stable in the formulation of glycine with one or both of sucrose, trehalose and mannitol as a saccharide protecting agent; neutral amino acids such as alanine are also more stable.
  • the stability data of 2-8 °C provided by the present invention is based on the raw material medicine produced by the company, wherein the raw material medicine contains process impurities such as RRT0.95 (relative retention time is 0.95), No change will occur during the stability investigation, and it will not affect the stability judgment. This is why the relative peak area of caspofungin provided by CN101516387A is higher than the data provided in this test.
  • the stabilized caspofungin pharmaceutical composition disclosed in CN101516387A which provides stability data at 25 ° C and 2-8 ° C, wherein stability data is provided at 2-8 ° C, each of which is described Under this condition, the total impurity content of the composition generally does not increase and decrease, which is not in accordance with scientific laws or measurement errors.
  • Comparative Example 2 repeated tests were carried out in the same way as the best formulation, and it was found that the change was not obvious under the stability condition of 2-8 ° C, but the stability was found to be significantly worse than the present invention under high temperature stability conditions.
  • a pharmaceutical composition is provided.
  • the caspofungin pharmaceutical composition provided by the present inventors has a significant advantage in stability at high temperatures. 5% ⁇ Even less than 0.2% or less, the amount of the impurities of the formula II can be controlled below 0.25%, or even less than 0.2%.
  • Formulation 1 is a comparative test performed in Example 1 of US2010/0137197, which provides stability data which is the percentage of caspofungin content and 0, which is affected by the difference in the amount of filling between each bottle of sample. This value may exceed 100%, which has been confirmed by the stability value at 30 °C of Example 2-2 in Table 3-C.
  • the relative peak area of caspofungin % is less than 1, the value is generally higher than the value obtained in this test, so the numerical comparability is small.
  • the formulation repeated in this test did demonstrate that it has better stability, however, the caspofungin pharmaceutical compositions disclosed herein are significantly more stable than they.
  • the HPLC spectra of Cancidas R1571 and Formula 3 are shown in Figures 1-3.
  • Formulation 22 has the same composition as disclosed in the patent CN102166186A, and we found during the experiment that the stability of the formulation was significantly worse than the formulation disclosed in this patent.
  • the freeze-drying method of the disclosed caspofungin pharmaceutical composition uses a lower secondary drying temperature and a longer drying time in order to achieve lower moisture and Lower impurities.
  • the caspofungin pharmaceutical composition provided by the invention has good stability at normal temperature and high temperature, and the freeze-drying method can be carried out by using a higher secondary drying stage temperature, thereby improving the lyophilization efficiency and the total time consuming. It does not exceed 52 hours, or even more than 38 hours, and can provide superior stability to the composition, and the impurity content is also significantly lower than that of the existing caspofungin pharmaceutical composition which is lyophilized by a conventional freeze-drying method.

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Abstract

本发明公开了一种低杂质含量的卡泊芬净药用组合物，以及公开了制备这种低杂质含量的卡泊芬净药用组合物的方法。本发明提供的卡泊芬净药用组合物具有良好的稳定性。

Description

技术领域
本发明涉及治疗和 /或预防真菌感染的药用组合物， 同时涉及该药用组合 物的制备方法。 背景技术
棘白菌素，又称棘球白素，是一类新型抗真菌药， 属于乙酰六环类，为葡聚 糖合成酶抑药用组合物，非竞争性地抑制真菌细胞壁的 - β (1，3) -D-葡聚糖的 合成而发挥杀菌作用。 葡聚糖是一种真菌细胞壁多糖，是细胞壁的重要成分，它 能使细胞壁保持完整性并使其渗透压保持稳定。
卡泊芬净（caspofungin)是棘白菌素类抗真菌药的第一个产品， 其结构如 式 I，
Figure imgf000002_0001
其具有广谱抗真菌活性， 对白念珠菌、 非白念珠菌及曲霉属的真菌均有很 好的抗真菌活性， 对耐氟康唑、 两性霉素 B或氟胞嘧啶的念珠菌、 曲霉等也具 有体外抗菌活性。与唑类或多烯类无交叉耐药，对念珠菌分离株也无天然耐药， 适用于对其他治疗无效或不能耐受的侵袭性曲霉病。
最早开发卡泊芬净制剂的是美国的默沙东公司， 其卡泊芬净是以二醋酸盐 的形式进行给药， 已上市品商品名为 "科赛斯" （Canc idas ) 。 卡泊芬净的稳 定性很差， 极易降解产生杂质， 式 I I 降解杂质是主要降解杂质， 在注射用醋 酸卡泊芬净的进口药品注册标准 （标准号： JX20050258 ) 中以 L-747969标明， 其相对保留时间为 RRT1. 67。 在美国 FDA 公开的 "科赛斯 （CANCIDAS ) " 的 " HIGHLIGHTS OF PRESCRIBING INFORMATION" 中， 进一步表明 L- 747969是一 个开环的多肽化合物。在文献" Metabol ites of Caspofungin Acetate, a Potent Antifungal Agent, in Human Plasma and Urine " 中进一步表明， 该卡泊芬 净的主要降解杂质， 即开环的多肽化合物的结构如式 II所示。
美国专利 US5952300和 US6136783公开了一种含乙酸盐缓冲体系和赋形剂 的卡泊芬净药用组合物， 以及这种药用组合物在药学上的适应症。 该专利公开 了： 卡泊芬净药用组合物因含有乙酸盐缓冲剂而不是酒石酸盐缓冲剂， 而使该 药用组合物稳定。 然而其对组合物的稳定性情况和降解杂质情况未进行详细说 明和限定。 参考文献 US2010137197 公开了另一种更稳定的卡泊芬净药用组合 物。 该组合物因含有一种或多种玻璃化转变温度高于 90°C的非还原性糖， 以及 PH5-7 的乙酸盐缓冲体系而使该组合物更稳定， 其稳定性明显好于 US5952300 和 US6136783所公开的药用组合物。 然而这篇参考文献中也没有公开对卡泊芬 净的式 I I 降解杂质以及降解杂质 RRT1. 35 进行说明与限定。 中国专利 CN102166186A公开了另一种更稳定的卡泊芬净注射制剂组合物，该组合物因含 有山梨醇或山梨醇与其它赋形剂的混合物， 而使稳定性表现更优。 然而该配方 组合物在我们进行配方摸索的过程中曾经已进行过实验， 发现该组合物的稳定 性并不如人意， 其稳定性要明显差于本专利公开的配方。
参考文献 US20090324635公开了一种不含杂质 A (式 II I ) 的卡泊芬净， 以及制备这种卡泊芬净的方法。专利 US20090291996公开了一种不含杂质 C。（式 IV) 的卡泊芬净， 以及制备这种卡泊芬净和其药用组合物的方法。 这两篇专利 也未对卡泊芬净的式 Π 降解杂质和 RRT1. 35 的降解杂质进行说明与分析， 且 其是针对原料药而言。 参考文献 US20090170753公开了另一种稳定的卡泊芬净 药用组合物， 其含有额外的用量低于 0. 3摩尔当量的卡泊芬净盐的 pH调节剂 和有效形成冻干饼状物的药学上可接受量的赋形剂， 其认为所述的药用组合物 因含有额外的较少量的乙酸盐 pH 调节剂而具有更好的稳定性。 其对降解杂质 CAF-42进行了测定， 通过分析该杂质应为式 I I表示的杂质。 其公开的该杂质 的量在 0时最低为 0. 27%， 25°C下稳定性考察， 该杂质有明显增加， 2-8°C下稳 定性考察， 该杂质却反而不增反降， 尤其是其中的配方 4下降明显， 有悖常理， 其数据可信度值得商榷。
Figure imgf000004_0001
活性药物成分中的杂质， 如卡泊芬净中的杂质是人们所不期望的， 这些杂 质甚至有可能对患者产生安全性隐患。然而，要完全去除这些杂质是不现实的， 因此， 降低这些杂质的限度是药物制剂开发者的重点关注目标。
然而， 现已公开的各药用组合物并不是最理想的配方， 它们对卡泊芬净的 主要降解杂质未进行有效的严格控制， 且其稳定性还有待于进一步的提高。 因 此有必要开发一种新的药用组合物及制备工艺， 可以有效降低卡泊芬净的主要 降解杂质， 提高其安全性和稳定性， 延长药品的保存期。
本发明人在前期进行了大量的试验， 在卡泊芬净药用组合物的稳定性问题 上取得了很大的进展。
本发明提供了一种低杂质， 安全， 稳定， 可复制的冻干药用组合物， 及其 制备方法， 可直接用于治疗 /预防真菌感染。 发明内容
本发明提供一种包含式 I所示化合物和 /或其药学上可接受的盐的药用组合物， 其特征在于， 所述组合物中式 II杂质的 HPLC含量不超过 0. 25%;
Figure imgf000005_0001
Figure imgf000006_0001
I。
在一个具体实施方式中， 所述组合物中式 I I 杂质的 HPLC 含量不超过 0. 20%
在进一步的实施方式中， 所述组合物中式 II杂质的 HPLC含量不超过 0. 15%。 在另一实施方式中，式 I所示化合物的药学上可接受的盐为有机酸的酸加成盐 或其它形式的盐。
在另一实施方式中， 所述药用组合物为冻干制剂。
本发明还提供一种含有式 I所示化合物或其药学上可接受的盐的药用组合 物， 其中所述组合物包含糖类保护剂和氨基酸。
在一个具体实施方式中， 所述糖类保护剂为蔗糖、 海藻糖、 甘露醇中的一 种或多种。
在进一步的实施方式中， 所述糖类保护剂为蔗糖。
在另一实施方式中， 所述氨基酸为中性氨基酸。
在进一步的实施方式中，所述中性氨基酸选自以下的一种或以上：甘氨酸、 丙氨酸、 丝氨酸、 色氨酸、 酪氨酸和苏氨酸。
在还要进一步的实施方式中， 所述中性氨基酸为甘氨酸。
在具体的实施方式中， 所述糖类保护剂与式 I所示化合物或其药学上可接 受的盐的重量比为 60: 1-2: 1。
在进一步的实施方式中， 所述糖类保护剂与式 I所示化合物或其药学上可 接受的盐的重量比为 20: 1-4: 1。
在具体的实施方式中， 所述氨基酸与式 I所示化合物或其药学上可接受的 盐的重量比为 1 :8-4: 1。
在进一步的实施方式中， 所述氨基酸与式 I所示化合物或其药学上可接受 的盐的重量比为 1 :4-1.5: 1。
本发明还提供一种制备包含糖类保护剂和氨基酸的药用组合物的方法， 包 括以下步骤：
a. 将所述糖类保护剂和氨基酸溶于预冷的水中或适宜的缓冲溶液中； b. 加入式 I所示化合物使其溶解；
c 过滤步骤 b获得的溶液并在低温下装入小瓶中；
d. 冻干。
在具体的实施方式中， 所述糖类保护剂为蔗糖、 海藻糖、 甘露醇中的一种 或多种。
在进一步的实施方式中， 所述糖类保护剂为蔗糖。
在具体的实施方式中， 所述氨基酸为中性氨基酸。
在进一步的实施方式中，所述中性氨基酸选自以下的一种或以上：甘氨酸、 丙氨酸、 丝氨酸、 色氨酸、 酪氨酸和苏氨酸。
在还要进一步的实施方式中， 所述中性氨基酸为甘氨酸。
在具体的实施方式中， 所述糖类保护剂与式 I 所示化合物的重量比为
60: 1-2: 1。
在进一步的实施方式中， 所述糖类保护剂与式 I 所示化合物的重量比为 20: 1-4: 1。
在具体的实施方式中， 所述氨基酸与式 I所示化合物的重量比为 1 :8-4: 1。 在进一步的实施方式中， 所述氨基酸与式 I 所示化合物的重量比为
1 :4-1.5: 1。
在具体的实施方式中， 步骤 d所述的冻干过程为， 组合物经预冻和一次干 燥阶段后， 二次干燥阶段温度维持在 30°C -40°C， 且维持时间为 5-20小时， 冻 干总周期不超过 52小时。
在进一步的实施方式中， 所述二次干燥阶段温度维持在 35°C， 且维持时间 为 5-16小时， 冻干总周期不超过 38小时。
在具体的实施方式中， 步骤 d所述的冻干过程为：
a、 搁板温度以 0.1〜l °C/min的速度连续或间断的降至 -45〜- 40°C； b、 搁板温度在 -45〜- 40°C下维持 120〜180min;
c、 开启冷阱， 冷阱温度降至 -45 °C以下；
d、 开启真空度， 真空度降至 160mTor以下； e、 搁板温度以 0.1〜l°C/min的速度连续或间断升至 -30〜- 10°C； f、 搁板温度在 -30〜- 10°C下的单个和多个温度下共维持 960-1620min; g、 搁板温度以 0.04- l°C/min的速度升至 30-40 °C; 和
h、 搁板温度在 30-40 °C下维持 300-960min。 在更具体的实施方式中， 步骤 d所述的冻干过程为：
a、 搁板温度以 l°C/min的速度降至 -40°C;
b、 搁板温度在 -40°C下维持 120min;
c、 开启冷阱， 冷阱温度降至 -45°C以下；
d、 开启真空度， 真空度降至 80mTor以下；
e、 搁板温度以 0.1°C/min的速度升至 -20°C;
f、 搁板温度在 -20°C下维持 540-840min;
g、 搁板温度以 0.1°C/min的速度升至 -10°C;
h、 搁板温度在 -10°C下维持 420-780min;
i、 搁板温度以 0.04-0. l°C/min的速度升至 30-40 °C；
j、 搁板温度在 30-40 °C下维持 300-960min; 和
k、 干燥结束后压塞， 出箱， 轧盖；
或者步骤 d所述的冻干过程为：
a、 搁板温度以 l°C/min的速度降至 -5°C;
b、 搁板温度在 -5°C下维持 30min;
c、 搁板温度以 l°C/min的速度降至 -45°C;
d、 搁板温度在 -45°C下维持 150min;
e、 开启冷阱， 冷阱温度降至 -45°C以下；
f、 开启真空度， 真空度降至 160mTor以下；
g、 搁板温度以 0.1°C/min的速度升至 -30°C;
h、 搁板温度在 -30°C下维持 960min;
i、 搁板温度以 l°C/min的速度升至 35°C;
j、 搁板温度在 35°C下维持 300min;
k、 真空度降至 20mTor以下；
1、 搁板温度在 35°C下维持 300min; 和
m、 干燥结束后压塞， 出箱， 轧盖。 本发明还提供上述任一种药用组合物在制备预防和 /或治疗哺乳动物真菌 感染的药物中的用途。 附图说明
图 1是对比例 1中的 Cancidas 1571的 HPLC图谱。
Figure imgf000009_0001
图 2是实施例中的配方 3在 25°C下 24周的 HPLC图谱。
Figure imgf000009_0002
图 3是实施例中的配方 3 在 2-8 °C下 24周的 HPLC图谱。
Figure imgf000009_0003
具体实施方式
本发明人在对棘白菌素类抗真菌化合物卡泊芬净的化学稳定性研究过程 中， 尝试了不同的赋形剂， 并对赋形剂的含量与含卡泊芬净的组合物的稳定性 的之间的关系进行了研究， 令人意外的发现包含卡泊芬净或其药学上可接受的 盐和糖类保护剂和氨基酸的药用组合物令人意外的稳定， 其稳定性甚至优于已 有报道的该物质的各种组合物， 其降解杂质的含量能够得到有效的控制。 在此 基础上， 完成了本发明。
本文所用的术语 "预冻"是指将液态产品中的水分全部固化的过程， 以便 在真空下进行升华。 "一次干燥"是指通过对产品加热， 去除溶质间的自由水， 使固态冰升华为水蒸汽的过程， 该阶段能去除大约 90%的水分。 "二次干燥" 又称解吸干燥， 是指当产品内冻结的冰大部分升华完毕， 继续提高加热温度， 去除产品内部的部分结合水， 使产品水分达到要求的过程。 此过程中温度的提 高有利于提高工作效率。 但由于醋酸卡泊芬净的热稳定性较差， 因此， 常用冻 干方法的二次干燥阶段温度维持在较低的水平， 如 25°C， 甚至是 15°C， 造成 了总冻干周期较长的不利因素。 本发明公开的冻干方法突破了常规的方法， 采 用了较高的二次干燥温度， 并采用的一定的升温速率， 最终不但降低了杂质的 产生， 也提高了工作效率。
在一个实施方案中， 通过对卡泊芬净的市售商品 "科赛斯" （Cancidas) 进行 HPLC分析得知， "科赛斯"中含 0.31%面积比的式 II杂质， 式 II的杂质 是卡泊芬净的主要降解杂质， 是卡泊芬净脱乙二胺开环后的产物， 其降解过程 受温度和水分的影响很大， 在卡泊芬净的药用组合物的制备过程中极易产生。
本发明提供的药用组合物及其制备方法能够较好的避免卡泊芬净的降解， 并能较好的提供该药用组合物的稳定性。
本发明提供了一种包含式 I所示化合物和 /或其药学上可接受的盐的药用组合 物， 所述组合物中式 II杂质的 HPLC含量不超过 0.25%; 优选不超过 0.20%; 更优 的不超过 0.15%。
本发明的组合物中所述式 II杂质的 HPLC相对保留时间 （RRT) 为 1.64—
1.70。
本发明提供的药物组合物， 其包含：
a) 式 I所示卡泊芬净或其药学上可接受的盐， 和
b) 糖类保护剂和氨基酸。
所述糖类保护剂选自： 蔗糖、 海藻糖、 甘露醇中的一种或多种， 优选蔗糖。 所述氨基酸优选中性氨基酸， 更优选以下的一种或以上： 甘氨酸、丙氨酸、 丝氨酸、 色氨酸、 酪氨酸和苏氨酸； 最优的为甘氨酸。
本发明的组合物优选包含糖类保护剂与卡泊芬净或其药学上可接受的盐 的重量比为 60:1-2:1; 更优选糖类保护剂与卡泊芬净或其药学上可接受的盐的 重量比为 20:1-4:1。
本发明的组合物优选包含氨基酸与卡泊芬净或其药学上可接受的盐的重量比 为 1:8-4:1; 更优选氨基酸与卡泊芬净或其药学上可接受的盐的重量比为 1:4- 1· 5: 1。
本发明提供的药物组合物还可以含有额外的 pH调节剂， 如磷酸盐缓冲剂、 乙酸盐缓冲剂、 柠檬酸盐缓冲剂等药学上可接受的 pH调节剂。 缓冲剂的 pH范 围优选 5-7， 更优选 5.5-6.5。 本发明提供的药物组合物可通过冻干获得的冻干粉。 该冻干粉可通过用水 溶液再溶解成肠胃外、 优选静脉内施用的液体组合物。
所述的水溶液优选无菌注射用水， 任选包含对羟基苯甲酸甲酯和 /或对羟 基苯甲酸丙酯和 /或 0. 9%苄醇的抑菌注射用水， 或生理盐水（normal sal ine) 或生理盐水（phys iologi cal sal ine)，例如 0. 9%氯化钠溶液，或 0. 45%或 0. 225% 氯化钠溶液， 或林格液， 和 /或林格乳酸盐溶液。
本发明进一步提供了本发明组合物在制备用于预防和 /或治疗哺乳动物， 优选人因假丝酵母属物种和 /或曲霉属物种和 /或杰氏肺囊虫导致的真菌感染 或病症的药物、 优选静脉内药物中的用途。
本发明的组合物可以进一步包含另一种， 例如一种或多种药学上可接受的 赋形剂， 包括本领域中公知的稀释剂或载体， 它们适合于预期用于肠胃外施用 的组合物， 诸如用于肌内、 皮下、 静脉内、 腹膜内或肌内施用的可注射药用组 合物。 这类赋形剂可以包括， 例如抗氧化剂、 张皮剂、 防腐剂、 碳水化合物、 蜡、 水溶性和 /或可溶胀聚合物、 亲水性或疏水性材料、 明胶、 油、 溶剂、 水 等。
合适的溶剂或稀释剂包括， 但不限于含水溶剂， 优选包含对羟基苯甲酸甲 酯和 /或对羟基苯甲酸丙酯和 /或 0. 9%苄醇的抑菌注射用水， 或生理盐水 (normal sal ine)或生理盐水（phys i ological sal ine) ，例如 0. 9%氣化销溶液， 或 0. 45%或 0. 225%氯化钠溶液， 或林格液， 和 /或林格乳酸盐溶液。 这些溶剂 和 /或稀释剂还可以用于再溶解冻干粉形式的本发明组合物和 /或用于进一步 稀释由此获得的再溶解溶液。
本文所用的术语"卡泊芬净"意指卡泊芬净游离碱。 例如， 卡泊芬净的药学 上可接受的盐描述在 EP0620232中。 本发明还包括其溶剂合物和 /或水合物。
本文所用的术语"卡泊芬净的药学上可接受的盐"意指卡泊芬净的无毒性 盐， 优选卡泊芬净的药学上可接受的盐为与有机酸的酸加成盐， 所述的有机酸 选自乙酸、 柠檬酸、 酒石酸、 丙酸、 草酸、 苹果酸、 马来酸、 乳酸、 谷氨酸。 最优选卡泊芬净的药学上可接受的盐为卡泊芬净二乙酸盐。
本文所用的术语"中性氨基酸"是指分子中碱性的" -NH2 "与酸性的" -C00H" 数目相等的一类氨基酸。
本发明还提供了一种制备式 I I杂质含量不超过 0. 25% ( HPLC含量） 的卡 泊芬净药用组合物的方法， 其包含以下步骤： a. 将糖类保护剂和氨基酸溶于预冷的水中或适宜的缓冲溶液中； b. 加入式 I化合物使其溶解；
c 过滤步骤 b获得的溶液并在低温下装入小瓶中冻干；
d. 冻干过程中， 组合物经预冻和一次干燥阶段后， 二次干燥阶段温度维持在 30°C-40°C , 且维持时间为 5-20小时， 冻干总周期不超过 52小时。 优选组合物经 预冻和一次干燥阶段后，二次干燥阶段温度维持在 35°C，且维持时间为 5-16小时， 冻干总周期不超过 38小时。
由于卡泊芬净药用组合物对水分比较敏感， 因此必须对组合物充分干燥。 因考虑到卡泊芬净在常温和高温下极不稳定， 且现已公开的卡泊芬净药用组合 物在常温和高温下的稳定性也不够理想， 因此现有卡泊芬净药用组合物的常规 冷冻干燥方法， 其二次干燥阶段的温度通常维持在较低的温度进行， 如美国专 利 US2010137197所公开的， 其二次干燥阶段维持温度为 15°C， 最高的二次干 燥阶段维持温度也只是 25°C， 这就造成了其干燥效率低， 为了得到较低水分的 终产物， 其冻干总周期必定长等不利因素， 不利于实际生产。 本发明人通过大 量的试验摸索， 意外地发现采用本发明提供的药用组合物， 其高温下稳定性较 好， 其冷冻干燥方法可以采用较高的二次干燥阶段温度进行， 因此不但耗时较 短， 而且能够为组合物提供优越的稳定性。
综上所述， 本发明的主要优点在于：
1. 通过利用特定的赋形剂组合减少卡泊芬净药用组合物的制备和储存过 程中式 I I降解杂质的产生；
2. 相比于现有技术， 本发明的卡泊芬净药用组合物在常温下稳定， 为其 储存和运输带来便利；
3. 相比于现有技术， 本发明的卡泊芬净药用组合物能在较高温度下冻干， 从而加快了冻干流程， 有利于实际生产。 实施例
卡泊芬净 HPLC分析方法：
高效液相色谱仪： WATERS 2695-2998
分析柱： YMC- Pack 0DS- A柱， 规格： 250 X 4. 6mm， S- 5um， 1. 2nm
柱温： 35 °C
检测波长： 220nm 流动相： A: 0.1%的高氯酸 （分析纯， 上海金鹿化工有限公司） 和 0.075% 的氯化钠 （分析纯， 国药集团化学试剂有限公司） 溶液 （取高氯酸 1.0ml和氯 化钠 0.75g， 加水溶解并稀释到 1000ml) ；
B: 乙腈 （HPLC级， TEDIA) 。
梯度条件如下表所示：
Figure imgf000013_0001
流量为： lml/min或 1.45ml/min。 当流量为 1.45ml/min时， 主峰的保留 时间为 20min 左右， 与专利 US2010/0137197 等文献相同， 故 RRT 值采用 1.45ml/min流量时的值。 通过对比 lml/min和 1.45ml/min两种不同流量下的 图谱得知： 1.45ml/min流量时的 RRT1.67的峰为 lml/min流量的 RRT1.52的峰。
%相对峰面积， 即， HPLC含量， 为该峰的峰面积占总峰面积的百分比。 对比例 1
卡泊芬净已上市商品 "科赛斯" 的 HPLC分析
美国默沙东公司的已上市卡泊芬净制剂 "科赛斯" （Cancidas) 在有效期 内按照上述卡泊芬净 HPLC分析方法进行杂质分析。"科赛斯 "用乙腈：0.01mol/L 的醋酸钠溶液 =1: 4稀释至 0. lmg/ml, 在 5°C下注入上述液相色谱系统。 "科 赛斯" 中的式 II杂质情况如下:
Figure imgf000013_0002
对比例 2
以下对比例和实施例所用的原料均产自于上海天伟生物制药有限公司。 按照 US2010/0137197的实施例 1进行组合物的制备。 取海藻糖 1.20g溶 于 3ml水中， 之后加入 7.5μ1的冰醋酸， 用 1M的氢氧化钠调至 ρΗ5.1， 再加入 醋酸卡泊芬净 0.223g， 轻轻搅拌溶解， 并用 1M的氢氧化钠调至 pH6.0， 加水 定容到 5mL， 0.22μιη膜过滤， 冻干前的组合物 （配方 1) 的组成如下表： 醋酸卡泊芬净 （按卡泊芬净碱基计， 下同） 40mg/ml
海藻糖 240mg/ml
冰醋酸 1.5mg/ml
氢氧化钠 调至 pH6.0 配制好的溶液按 0.5mL/瓶分装至 2mL的抗生素瓶中， 用经 110°C烘过夜的 V50 4405/50 Grey Sil A胶塞 （购自西氏医药服务有限公司） 加塞后装盘放入 冷冻干燥机中进行冷冻干燥， 冷冻干燥程序如下 （冻干程序 F) ：
a、 搁板温度以 0.2°C/min的速度降至 -40°C;
b、 搁板温度在 -40°C下维持 120min;
c、 开启冷阱， 冷阱温度降至 -45°C以下；
d、 开启真空度， 真空度降至 80mTor以下；
e、 搁板温度以 0. rC/min的速度升至 -20°C;
f、 搁板温度在 -20°C下维持 3000min;
g、 搁板温度以 0. rC/min的速度升至 -15°C;
h、 搁板温度在 -15°C下维持 900min;
i、 搁板温度以 0. rC/min的速度升至 -10°C;
j、 搁板温度在 -10°C下维持 400min;
k、 搁板温度以 0. rC/min的速度升至 -5°C;
1、 搁板温度在 -5°C下维持 400min;
m、 搁板温度以 0. rC/min的速度升至 15°C;
n、 搁板温度在 15°C下维持 720min;
o、 搁板温度以 rC/min的速度升至 25°C;
p、 搁板温度在 25°C下维持 240min;
q、 干燥结束后压塞， 出箱， 轧盖。
冻干制品分别放置于 40°C进行稳定性考察， 并分别于 8周和 24周后取样 进行 HPLC分析， 以及分别于 25°C、 65%RH和 2-8°C条件下进行稳定性考察， 并 分别于 12周后取样进行 HPLC分析 (包括第 0时的数据)。 对比例 3
按照 CN101516387A的实施例 4进行组合物的制备。 取甘露醇 0. 5g、 蔗糖 0. 75g， 溶于 20ml水中， 之后加入 1. 05g的卡泊芬净碱， 即 1. 17g的醋酸卡泊 芬净， 不再调节 pH， 加水调准到 25mL终体积， 0. 22μιη膜过滤， 冻干前的组合 物 （配方 2 ) 的组成如下表：
醋酸卡泊芬净 42mg/ml
蔗糖 30mg/ml
甘露醇 20mg/ml 以 1. 25ml/瓶的量灌装至小瓶并冻干 （冻干程序同配方 1， 只是在最后 15
°C的运行完后， 即停止冻干， 不再升温至 25°C )。
冻干制品分别放置于 40°C进行稳定性考察， 并分别于 8周和 24周后取样 进行 HPLC分析， 以及分别于 25°C、 65%RH和 2-8°C条件下进行稳定性考察， 并 分别于 24周后取样进行 HPLC分析 (包括第 0时的数据)。 实施例 1
卡泊芬净药用组合物制备
配制过程为： 先将糖类保护剂和氨基酸溶于水中或溶于含有任选的 pH调节剂 溶液中， 再加入式 I化合物或其药学上可接受的盐使其溶解， 定容到一定的体积， 之后冻干前面所获得的溶液。
通过变化卡泊芬净的浓度和 /或糖类保护剂和 /或甘氨酸 （或其他氨基酸） 的浓度， 以及 pH调节剂的 pH或浓度得到不同的配方。 冻干前的组合物各配方 的组成如下表：
Figure imgf000016_0001
Figure imgf000017_0001
各冻干程序如下：
冻干程序 A:
a、 搁板温度以 rC/min的速度降至 -40°C; b、 搁板温度在 -40°C下维持 120min;
c、 开启冷阱， 冷阱温度降至 -45°C以下； d、 开启真空度， 真空度降至 80mTor以下； e、 搁板温度以 0. rC/min的速度升至 -20°C; f、 搁板温度在 -20°C下维持 540min;
g、 搁板温度以 0. rC/min的速度升至 -10°C; h、 搁板温度在 -10°C下维持 420min;
i、 搁板温度以 0. rC/min的速度升至 35°C; j、 搁板温度在 35°C下维持 960min;
k、 干燥结束后压塞， 出箱， 轧盖。 冻干程序 B:
a、 搁板温度以 rC/min的速度降至 -40°C; b、 搁板温度在 -40°C下维持 120min;
c、 开启冷阱， 冷阱温度降至 -45°C以下； d、 开启真空度， 真空度降至 SOmTor以下； e、 搁板温度以 0. rC/min的速度升至 -20°C; f、 搁板温度在 -20°C下维持 540min;
g、 搁板温度以 0. rC/min的速度升至 -10°C; h、 搁板温度在 -10°C下维持 420min;
i、 搁板温度以 0.04°C/min的速度升至 35°C; j、 搁板温度在 35°C下维持 300min;
k、 干燥结束后压塞， 出箱， 轧盖。 冻干程序 C:
a、 搁板温度以 0. rC/min的速度降至 -40°C; b、 搁板温度在 -40°C下维持 120min;
c、 开启冷阱， 冷阱温度降至 -45C以下； d、 开启真空度， 真空度降至 80mTor以下； e、 搁板温度以 0. rC/min的速度升至 -20°C; f、 搁板温度在 -20°C下维持 840min;
g、 搁板温度以 0. rC/min的速度升至 -10°C; h、 搁板温度在 -10°C下维持 780min;
i、 搁板温度以 0. rC/min的速度升至 30°C; j、 搁板温度在 30°C下维持 600min;
k、 干燥结束后压塞， 出箱， 轧盖。 冻干程序 D:
a、 搁板温度以 rC/min的速度降至 -40°C; b、 搁板温度在 -40°C下维持 120min;
c、 开启冷阱， 冷阱温度降至 -45°C以下； d、 开启真空度， 真空度降至 80mTor以下； e、 搁板温度以 0. rC/min的速度升至 -20°C; f、 搁板温度在 -20°C下维持 700min;
g、 搁板温度以 0. rC/min的速度升至 -10°C; h、 搁板温度在 -10°C下维持 660min;
i、 搁板温度以 0. rC/min的速度升至 40°C; j、 搁板温度在 40°C下维持 600min;
1、 干燥结束后压塞， 出箱， 轧盖。 冻干程序 E:
a、 搁板温度以 rC/min的速度降至 -5°C; b、 搁板温度在 -5°C下维持 30min;
c、 搁板温度以 rC/min的速度降至 -45°C; d、 搁板温度在 -45°C下维持 150min;
e、 开启冷阱， 冷阱温度降至 -45°C以下； f、 开启真空度， 真空度降至 160mTor以下； g、 搁板温度以 0. rC/min的速度升至 -30°C; h、 搁板温度在 -30°C下维持 960min; 搁板温度以 rC /min的速度升至 35°C ;
m k j 1
搁板温度在 35°C下维持 300min;
真空度降至 20mTor以下；
搁板温度在 35°C下维持 300min;
干燥结束后压塞， 出箱， 轧盖。 各个配方冻干完后， 同样进行对比例 2中所述的稳定性考察。 实施例 2
取 0. 75g山梨醇， 0. 5g甘露醇， 溶于 20ml水中， 之后加入 1. 05g的卡泊 芬净碱， 然后加入磷酸二氢钠， 至其最终定容浓度为 20mM， 并用氢氧化钠调 pH至 6. 0， 加水定容到 25mL终体积。 再经 0. 22μιη滤膜过滤， 冻干前的组合物 (配方 22 ) 的组成如下表：
卡泊芬净碱 42mg/ml
山梨醇 30mg/ml
甘露醇 20mg/ml
磷酸二氢钠 20mM
氢氧化钠 调 ρΗ6· 0 冻干制品分别放置于 40°C进行稳定性考察， 并分别于 8周和 24周后取样 进行 HPLC分析， 以及分别于 25°C、 65%RH和 2-8°C条件下进行稳定性考察， 并 分别于 24周后取样进行 HPLC分析 (包括第 0时的数据)。 实施例 3
卡泊芬净药用组合物稳定性
对比例 2、 3和 4以及实施例 1的样品分别进行稳定性考察后， 用 HPLC对样品 进行分析。
40°C稳定性试验结果如下表所示:
8周时卡泊芬 24周时卡泊芬
0时卡泊芬净
配方编号 温度 /°c 净 /%相对峰面 净 /%相对峰面
/%相对峰面积
积 积
1 40 99.17 94.22 85.98 2 40 99.10 87.39 79.31
3 40 99.29 98.83 97.76
4 40 99.26 98.79 97.91
5 40 99.25 98.82 97.93
6 40 99.27 98.77 97.93
7 40 99.24 98.72 97.87
8 40 99.25 98.76 97.95
9 40 99.27 98.65 97.88
10 40 99.26 98.82 97.97
1 1 40 99.25 98.70 97.82
12 40 99.20 97.83 96.75
13 40 99.23 98.37 96.86
14 40 99.25 98.08 96.24
15 40 99.26 98.63 97.57
16 40 99.23 98.53 97.52
17 40 99.27 98.79 97.87
18 40 99.25 98.82 97.93
19 40 99.22 98.71 97.78
20 40 99.24 98.67 97.65
21 40 99.27 98.71 97.72
22 40 99.13 88.23 81.44
40°C稳定性考察后， 由于卡泊芬净％相对峰面积降低较多， 杂质情况较复 ， 进行单个杂质对比已无意义， 故未列出式 I I杂质的相关数据
25 °C稳定性试验结果如下表所示：
卡泊芬净 /%相对峰面积 式 II杂质 /%相对峰面积 配方编号
0时 24周 0时 24周
1 99.17 97.26 0.27 0.56
2 99.10 96.75 0.29 0.73
3 99.27 99.14 0.13 0.18
4 99.26 99.15 0.14 0.18
5 99.25 99.17 0.15 0.18
6 99.27 99.14 0.13 0.17
7 99.24 99.17 0.17 0.20
8 99.25 99.13 0.15 0.17
9 99.27 99.15 0.14 0.19
10 99.26 99.16 0.14 0.19
1 1 99.25 99.1 1 0.15 0.23
12 99.20 98.91 0.25 0.49
13 99.23 99.13 0.14 0.23
14 99.25 99.10 0.17 0.25
15 99.26 99.14 0.12 0.21
16 99.23 99.13 0.14 0.21
17 99.20 99.16 0.14 0.18
18 99.25 99.12 0.13 0.23 19 99.22 99.05 0.16 0.28
20 99.24 99.09 0.14 0.25
21 99.27 99.1 1 0.19 0.24
22 99.13 97.15 0.31 0.66
2-8°C稳定性试验结果如下表所示:
Figure imgf000022_0001
通过对比以上稳定性试验数据可知： 添加甘氨酸的各个配方在 2-8°C条件 下都非常稳定， 24周后卡泊芬净含量都没有明显的降低。 以蔗糖、 海藻糖、 甘 露醇其中一种或两种作为糖类保护剂添加甘氨酸的配方中蔗糖甘氨酸配方表 现得最稳定； 添加丙氨酸等中性氨基酸表现得也较稳定。 本发明所提供的 2-8 °C稳定性数据是基于本公司生产的原料药的基础上进行的， 其中原料药中含有 RRT0. 95 (相对保留时间为 0. 95 ) 等的工艺杂质， 其在稳定性考察过程中不会 发生变化， 不会影响稳定性的判断。 这也正是 CN101516387A提供的卡泊芬净％ 相对峰面积高于本试验提供的数据的原因。
CN101516387A所公开的稳定卡泊芬净药用组合物，因其提供的稳定性条件 为 25°C和 2-8 °C， 其中 2-8°C下提供了稳定性数据， 其所描述的各组合物在该 条件下， 总杂质含量普遍不增反降， 不符合科学规律或者是测量误差所致。 我 们在对比例 2 中仿照其最好的配方进行重复试验， 发现其在 2-8°C的稳定性条 件下变化不明显， 但在高温稳定性条件下发现其稳定性明显要差于本发明提供 的药用组合物。 另外， 在 2-8°C下稳定的配方， 由于在实际生产和运输过程存 在着许多困难， 因此， 本发明人致力于摸索出在常温下较稳定的配方。 通过上 述 40°C和 25°C的稳定性数据可知， 本发明人所提供的卡泊芬净药用组合物在 高温下的稳定性有明显的优势。 另外， 本发明所公开的药用组合物， 在经过 25 24周的稳定性考察后， 其式 II所示的杂质都能够控制在 0. 25%以下， 甚至 是 0. 2%以下。
另外， 配方 1是重复 US2010/0137197的实施例 1进行的对比试验， 其提供的 稳定性数据是卡泊芬净的含量与 0时的百分比， 受每瓶样品之间的灌装量差异 的影响， 该值可能会超过 100%， 这已经由其表 3-C中例 2-2的 30°C下的稳定性数 值得到了证实。 另外， 考虑到 0时的卡泊芬净％相对峰面积小于 1， 因此其数值 会普遍高于本试验所得数值， 故其数值可比性较小。 本试验所重复的该配方确 实证明了其具有较好稳定性， 然而本发明所公开的卡泊芬净药用组合物明显比 其具有更优越的稳定性。 Cancidas R1571和配方 3的 HPLC图谱见附图 1〜3。
配方 22与专利 CN102166186A公开的配方组成相同， 我们在实验过程中发 现， 该配方的稳定性要明显差于本专利公开的配方。
由于卡泊芬净对热极不稳定， 现已公开的卡泊芬净药用组合物的冷冻干燥方 法都采用较低的二次干燥温度和较长的干燥时间，以期达到较低的水分和较低的杂 质。本发明提供的卡泊芬净药用组合物在常温和高温下具有较好的稳定性，其冷冻 干燥方法可以采用较高的二次干燥阶段温度进行，提高了冻干效率，其总耗时不超 过 52小时， 甚至是不超过 38小时， 而且能够为组合物提供优越的稳定性， 杂质含 量也明显低于现有卡泊芬净药用组合物按常规冻干方法冻干后的产物。
以上所述仅为本发明的较佳实施例而已， 并非用以限定本发明的实质技术 内容范围， 本发明的实质技术内容是广义地定义于申请的权利要求范围中， 任 何他人完成的技术实体或方法， 若是与申请的权利要求范围所定义的完全相 同， 也或是一种等效的变更， 均将被视为涵盖于该权利要求范围之中。

Claims

权 利 要 求
1. 一种包含式 I所示化合物和 /或其药学上可接受的盐的药用组合物， 其特征 在于， 所述组合物中 II杂质的 HPLC含量不超过 0. 25%；
Figure imgf000024_0001
2. 如权利要求 1所述的药用组合物， 其特征在于， 所述组合物中式 II杂 质的 HPLC含量不超过 0. 20%。
3. 如权利要求 1所述的药用组合物， 其特征在于，所述组合物中式 II杂质的 HPLC含量不超过 0. 15%。
4. 如权利要求 1-3 中任一项所述的药用组合物， 其特征在于， 式 I所示化合 物的药学上可接受的盐为有机酸的酸加成盐或其它形式的盐。
5. 如权利要求 1-3 中任一项所述的药用组合物， 其特征在于， 所述药用组合 物为冻干制剂。
6. 一种含有式 I所示化合物或其药学上可接受的盐的药用组合物，其特征 在于， 所述组合物包含糖类保护剂和氨基酸。
7. 如权利要求 6所述的药用组合物，其特征在于，所述糖类保护剂为蔗糖、 海藻糖、 甘露醇中的一种或多种。
8. 如权利要求 7所述的药用组合物， 其特征在于， 所述糖类保护剂为蔗 糖。
9. 如权利要求 6所述的药用组合物， 其特征在于， 所述氨基酸为中性氨基 酸。
10. 如权利要求 9所述的药用组合物， 其特征在于， 所述中性氨基酸选自 以下的一种或以上： 甘氨酸、 丙氨酸、 丝氨酸、 色氨酸、 酪氨酸和苏氨酸。
11. 如权利要求 10所述的药用组合物， 其特征在于， 所述中性氨基酸为 甘氨酸。
12. 如权利要求 6-11中任一项所述的药用组合物， 其特征在于， 所述糖类 保护剂与式 I所示化合物或其药学上可接受的盐的重量比为 60: 1-2: 1。
13. 如权利要求 12所述的药用组合物， 其特征在于， 所述糖类保护剂与 式 I所示化合物或其药学上可接受的盐的重量比为 20: 1-4: 1。
14. 如权利要求 6-11中任一项所述的药用组合物， 其特征在于， 所述氨基 酸与式 I所示化合物或其药学上可接受的盐的重量比为 1 :8-4: 1。
15. 如权利要求 14所述的药用组合物， 其特征在于， 所述氨基酸与式 I所 示化合物或其药学上可接受的盐的重量比为 1 :4-1.5: 1。
16. 一种制备权利要求 6所述药用组合物的方法， 其特征在于， 所述制备 方法包括以下步骤：
a. 将所述糖类保护剂和氨基酸溶于预冷的水中或适宜的缓冲溶液中；
b. 加入式 I所示化合物使其溶解；
c 过滤步骤 b获得的溶液并在低温下装入小瓶中；
d. 冻干。
17. 如权利要求 16所述的方法， 其特征在于， 所述糖类保护剂为蔗糖、 海藻糖、 甘露醇中的一种或两种。
18. 如权利要求 17所述的方法， 其特征在于， 所述糖类保护剂为蔗糖。
19. 如权利要求 16所述的方法， 其特征在于， 所述氨基酸为中性氨基酸。
20. 如权利要求 19所述的方法， 其特征在于， 所述中性氨基酸选自以下 的一种或以上： 甘氨酸、 丙氨酸、 丝氨酸、 色氨酸、 酪氨酸和苏氨酸。
21. 如权利要求 20所述的药用组合物， 其特征在于， 所述中性氨基酸为甘 氨酸。
22. 如权利要求 16-21 中任一项所述的方法， 其特征在于， 所述糖类保护 剂与式 I所示化合物的重量比为 60: 1-2: 1。
23. 如权利要求 22所述的方法， 其特征在于， 所述糖类保护剂与式 I所示 化合物的重量比为 20: 1-4: 1。
24. 如权利要求 16-21 中任一项所述的方法， 其特征在于， 所述氨基酸与 式 I所示化合物的重量比为 1 :8-4: 1。
25. 如权利要求 24所述的方法， 其特征在于， 所述氨基酸与式 I所示化合 物的重量比为 1 :4-1.5: 1。
26. 如权利要求 16所述的方法， 其特征在于， 步骤 d所述的冻干过程为， 组合物经预冻和一次干燥阶段后， 二次干燥阶段温度维持在 30°C -40°C， 且维 持时间为 5-20小时， 冻干总周期不超过 52小时。
27. 如权利要求 26所述的方法， 其特征在于， 所述二次干燥阶段温度维持 在 35°C， 且维持时间为 5-16小时， 冻干总周期不超过 38小时。
28. 如权利要求 16所述的方法， 其特征在于， 步骤 d所述的冻干过程为： a、 搁板温度以 0.1〜l °C/min的速度连续或间断的降至 -45〜- 40°C；
b、 搁板温度在 -45〜- 40°C下维持 120〜180min;
c、 开启冷阱， 冷阱温度降至 -45 °C以下；
d、 开启真空度， 真空度降至 160mTor以下；
e、 搁板温度以 0.1〜l °C/min的速度连续或间断升至 -30〜- 10°C；
f、 搁板温度在 -30〜- 10°C下的单个和多个温度下共维持 960-1620min; g、 搁板温度以 0.04- l °C/min的速度升至 30-40 °C ; 和
h、 搁板温度在 30-40 °C下维持 300-960min。
29. 权利要求 1-14中任一项所述的药用组合物在制备预防和 /或治疗哺乳动 物真菌感染的药物中的用途。
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