WO2013044788A1 - 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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WO2013044788A1
WO2013044788A1 PCT/CN2012/081951 CN2012081951W WO2013044788A1 WO 2013044788 A1 WO2013044788 A1 WO 2013044788A1 CN 2012081951 W CN2012081951 W CN 2012081951W WO 2013044788 A1 WO2013044788 A1 WO 2013044788A1
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pharmaceutical composition
amino acid
temperature
formula
compound
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PCT/CN2012/081951
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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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Priority to ES201490034A priority Critical patent/ES2519240B1/es
Priority to DE112012003996.3T priority patent/DE112012003996T5/de
Priority to IN893KON2014 priority patent/IN2014KN00893A/en
Priority to US14/346,268 priority patent/US9149502B2/en
Priority to KR1020147011189A priority patent/KR101660603B1/ko
Publication of WO2013044788A1 publication Critical patent/WO2013044788A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08Peptides having 5 to 11 amino acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19Particulate 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10Antimycotics
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56Cyclic 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 treating and/or preventing fungal infections, and to a process for the preparation of the pharmaceutical composition. Background technique
  • Echinocandin also known as echinocandin, is a new class of antifungal drugs belonging to the acetylhexacyclic group, a glucan synthase inhibitory pharmaceutical composition that non-competitively inhibits the fungal cell wall- ⁇ (1 , 3) - ⁇ - glucan synthesis to play a bactericidal effect.
  • Glucan is a fungal cell wall polysaccharide that is an important component of the cell wall. It maintains the integrity of the cell wall and keeps its osmotic pressure stable.
  • Caspofungin (caspofungin) is the first product of echinocanin antifungal drugs.
  • 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".
  • Cancidas The stability of caspofungin is very poor, it is highly prone to degradation, producing a variety of degradation impurities, RRT (relative retention time) 1.35 degradation impurities are the main one.
  • RRT relative retention time 1.35 degradation impurities
  • 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 having a pH of 5-7, and the stability is significantly better than US5952300.
  • this reference does not disclose or limit the degradation of RSP (relative retention time) 1.35 of caspofungin.
  • Degradation of impurities RRT1.35 has a characteristic absorption peak as shown in Fig. 4 according to the PDA (absorption spectrum) spectrum. It is similar to the characteristic absorption peak of the compound of the formula I, and the characteristic absorption peak of the compound of the formula I is shown in Fig. 5.
  • the reference US20090324635 discloses a caspofungin free of impurities A (formula II) and a process for preparing such caspofungin.
  • Reference US20090291996 discloses a caspofungin free of impurities Co (formula III), and a process for preparing such caspofungin and a pharmaceutical composition thereof. These two patents also do not describe and analyze the degraded impurities of the formula II of caspofungin and the degradation impurities of RRT 1.35, and it is for the bulk drug. No.
  • US20090170753 discloses another stable caspofungin pharmaceutical composition containing an additional amount of a pH adjusting agent in an amount of less than 0.3 molar equivalents of caspofungin and a pharmaceutically effective lyophilized cake.
  • An acceptable amount of excipient which is believed to have better stability due to the inclusion of an additional minor amount of acetate pH adjusting agent. It measured the degradation impurity CAF-42, but did not explain and limit the impurities of RRT 1.35.
  • Chinese patent CN102166186A discloses another more stable caspofungin injection formulation composition which exhibits better stability performance by containing a mixture of sorbitol or sorbitol and other excipients. However, the composition of this formulation has also been tested in the course of our formulation and found that the stability of the composition is not satisfactory, and its stability is significantly worse than the formulation disclosed in this patent.
  • 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 do not provide effective and strict control of the crustyl ethyl T1.35 degradation impurities. Therefore, it is necessary to develop a new pharmaceutical composition and process, which can reduce the HPLC content of caspofungin RRT 1.35 degradation impurities, 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 The preparation method can be directly used for treating/preventing fungal infections.
  • 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 having a relative retention time of about 1.35 under the following HPLC conditions is not More than 0.10%;
  • the HPLC content of the impurities having a relative retention time of about 1.35 in the composition does not exceed 0.05%.
  • 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.
  • HPLC conditions are:
  • Mobile phase A: 0.1% perchloric acid and 0.075% sodium chloride solution
  • the flow rate is 1.45 ml/min. Adjust the chromatographic system so that the main peak retention time is about 20 minutes.
  • the invention also provides 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 weight ratio of said amino acid to a compound of formula I or a pharmaceutically acceptable salt thereof is from 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 protecting agent is one or more selected from the group consisting 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 following: 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 from 60:1 to 2:1.
  • the weight ratio of the saccharide protecting agent to the compound of formula I is
  • 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 from 1:4 to 1.5:1.
  • 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;
  • the shelf temperature is continuously or intermittently increased to -30 ⁇ -10 °C at a rate of 0.1 ⁇ 1 °C/min;
  • the shelf temperature is maintained at 960 ⁇ 10 °C at a single temperature and a total of 960-1620min; g, the shelf temperature is increased to 30-40 ° C at a rate of 0.04-rC / min ;
  • the shelf temperature is maintained at 30-40 ° C for 300-960 min.
  • 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; g, 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 raised to 30-40 °C at a rate of 0.04-0. rC/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 fungal infections in a mammal.
  • Figure 1 is an HPLC chromatogram of Cancidas R1571 in Comparative Example 1.
  • Figure 2 is an HPLC chromatogram of Formulation 3 in the Example at 25 °C for 24 weeks.
  • Figure 4 is a characteristic absorption peak of RRT 1.35 impurity.
  • Figure 5 is a characteristic absorption peak of the compound of formula I. detailed description
  • 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.
  • RRT relative retention time
  • 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 increase in temperature during this process is beneficial to improve 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 RRT 1.35 degradation impurity has an HPLC content of no more than 0.10%, more preferably RRT 1.35 degradation HPLC The content does not exceed 0.05%.
  • the HPLC relative retention time (RRT) of the RRT 1.35 degradation impurities in the compositions of the present invention is 1.32-1.37.
  • the pharmaceutical composition provided by the present invention comprises:
  • the amino acid is preferably a neutral amino acid; more preferably one or more selected from the group consisting of glycine, alanine, serine, tryptophan, tyrosine and threonine; most preferred is glycine.
  • the saccharide protecting agent is selected from one or more of sucrose, trehalose, and mannitol, preferably sucrose.
  • 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 from 5 to 7, more preferably from 5.5 to 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 administration, preferably intravenous administration, by a solution with water.
  • the aqueous solution is preferably sterile water for injection, optionally comprising bacteriostatic water for injection of methylparaben and/or propylparaben and/or 0.9% benzyl alcohol, or normal saline or physiological Physiological saline, such as 0.9% sodium chloride solution, or 0.45% or 0.225% sodium chloride solution, or Ringer's solution, and/or Ringer's lactate solution.
  • the invention further provides a composition of the invention for the preparation of a fungal infection or condition caused by the prevention and/or treatment of a mammal, preferably a Candida species and/or a Aspergillus species and/or a Pneumocystis carinii.
  • 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 parenteral administration.
  • Compositions such as injectable pharmaceutical compositions 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 normal saline Or physiological saline, such as 0.9% sodium chloride solution, or 0.45% or
  • 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 a class of amino acids having the same number of basic "-NH 2 " and acidic "-COOH” in the molecule.
  • composition of the present invention preferably comprises a weight ratio of the saccharide protecting agent to caspofungin or a pharmaceutically acceptable salt thereof of 60: 1-2: 1 ; more preferably 20: 1-4: 1.
  • compositions of the present invention preferably comprise a weight ratio of amino acid to caspofungin or a pharmaceutically acceptable salt thereof of from 1:8 to 4:1. More preferably 1 : 4-1.5: 1.
  • the present invention also provides a method of preparing a crustine methyl pharmaceutical composition having an RRT 1.35 degradation impurity of no more than 0.10% (HPLC), comprising the steps of:
  • 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.
  • 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 peak of RRT 1.35 at a flow rate of 1.45 ml/min is the peak of RRT 1.26 at a flow rate of 1 ml/min.
  • % relative peak area, gp, 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 US2010/0137197. 1.20 g of trehalose was dissolved in 3 ml of water, then 7.5 ⁇ l of glacial acetic acid was added, adjusted to pH ⁇ 5.1 with 1 M sodium hydroxide, and then added with 0.223 g of caspofungin, dissolved by stirring, and treated with 1 M of hydrogen peroxide.
  • the sodium was adjusted to pH 6.0, and the solution was filtered to a volume of 5 mL, 0.22 ⁇ m, and the composition of the composition before lyophilization (Formulation 1) was as follows:
  • Caspofungin acetate (according to caspofungin base, the same below) 40mg/ml
  • Glacial acetic acid 1.5mg/ml Adjust the sodium hydroxide to ⁇ . ⁇ Dispense the prepared solution into a 2mL antibiotic bottle at 0.5mL/bottle, and use a V50 4405/50 Grey Sil A rubber stopper that was baked overnight at 10 °C (purchased from West's Pharmaceuticals). Service Co., Ltd.) After plugging, the plate is placed in a freeze dryer for freeze-drying.
  • the freeze-drying procedure is as follows (freeze-drying procedure F):
  • 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 0.1 °C/min;
  • the shelf temperature is maintained at -20 ° C for 3000 min;
  • the shelf temperature is raised to -15 ° C at a rate of 0.1 ° C / min;
  • the shelf temperature is maintained at -15 ° C for 900 min;
  • the shelf temperature is raised to -10 °C at a rate of 0.1 °C/min;
  • the shelf temperature is maintained at -10 ° C for 400 min;
  • the shelf temperature is raised to -5 °C at a rate of 0.1 °C / min;
  • the shelf temperature is maintained at -5 ° C for 400 min;
  • the shelf temperature is raised to 15 ° C at a rate of 0.1 ° C / min;
  • the shelf temperature is maintained at 15 ° C for 720min;
  • the shelf temperature is raised to 25 ° C at a rate of l ° C / min;
  • the shelf temperature is maintained at 25 ° C for 240 min;
  • composition of the composition before lyophilization is as follows: Caspofungin acetate 42mg/ml
  • Mannitol 20 mg/ml was filled into vials at 1.25 ml/vial and lyophilized (freeze-drying procedure with Formula 1, only after the last 15 °C run, the lyophilization was stopped and no longer heated to 25).
  • Example 1 The lyophilized products were placed at 40 ° C and 75% RH for stability investigation, and samples were taken for HPLC analysis at 8 and 24 weeks, respectively, and at 25 ° C, 60% RH and 2-8 ° C, respectively. Stability studies were performed and samples were taken for HPLC analysis after 12 weeks (including data at time 0).
  • Example 1 The lyophilized products were placed at 40 ° C and 75% RH for stability investigation, and samples were taken for HPLC analysis at 8 and 24 weeks, respectively, and at 25 ° C, 60% RH and 2-8 ° C, respectively. Stability studies were performed and samples were taken for HPLC analysis after 12 weeks (including data at time 0).
  • the preparation process is: first dissolving the saccharide protecting agent and glycine (or other amino acid) in water or in an aqueous solution containing an optional pH adjuster, and then adding the compound of the formula I or a pharmaceutically acceptable salt thereof to dissolve it.
  • the volume is set to a certain volume, and then the solution obtained before is freeze-dried.
  • composition of each formulation of the composition before lyophilization is as follows:
  • the shelf temperature is reduced to -40 ° C at a rate of l ° C / min; b, the shelf temperature is maintained at -40 ° C for 120 min;
  • the temperature of the cold trap drops below -45 °C; d, the vacuum is turned on, the vacuum is reduced to below 80mTor; e, the shelf temperature is raised to -20 °C at a rate of 0.1 °C / min; f, the shelf temperature is maintained at -20 ° C for 540 min;
  • the shelf temperature is raised to -10 ° C at a rate of 0.1 ° C / 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 0.1 ° C / 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 l ° C / min; b, the shelf temperature is maintained at -40 ° C for 120 min;
  • the temperature of the cold trap drops below -45 °C; d, the vacuum is turned on, the vacuum is reduced to below 80mTor; e, the shelf temperature is raised to -20 °C at a rate of 0.1 °C / min; f, the shelf temperature is maintained at -20 ° C for 540 min;
  • the shelf temperature is raised to -10 ° C at a rate of 0.1 ° C / 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. l ° C / min; b, the shelf temperature is maintained at -40 ° C for 120 min;
  • the temperature of the cold trap drops below -45 ° C; d, the degree of vacuum is turned on, the vacuum degree is reduced to below 80 mTor; e, the shelf temperature is raised to -20 ° C at a rate of 0.1 ° C / min; f, the shelf temperature is maintained at -20 ° C for 840 min;
  • the shelf temperature is raised to -10 ° C at a rate of 0.1 ° C / 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 0.1 ° C / 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 l ° C / min; b, the shelf temperature is maintained at -40 ° C for 120 min;
  • the temperature of the cold trap drops below -45 °C; d, the vacuum is turned on, the vacuum is reduced to below 80mTor; e, the shelf temperature is raised to -20 °C at a rate of 0.1 °C / min; f, the shelf temperature is maintained at -20 ° C for 700 min;
  • the shelf temperature is raised to -10 ° C at a rate of 0.1 ° C / 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 0.1 ° C / 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 l ° C / 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 l ° C / 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 160mTor; g, the shelf temperature is raised to -30 °C at a rate of 0.1 °C / min; h, the shelf temperature is maintained at -30 ° C for 960 min; i, 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;
  • 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
  • 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 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 2-8 °C stability data 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 RRT 0.95 (relative retention time of 0.95), and its stability.
  • a pharmaceutical composition is provided. Further, in the formulation which is stable at 2-8 ° C, the present inventors have made efforts to find a formulation which is relatively stable at normal temperature because of many difficulties in actual production and transportation. From the above stability data at 40 ° C and 25 ° C, it is known that the caspofungin pharmaceutical composition provided by the present inventors has a significant advantage in stability at high temperatures. In addition, the RRT 1.35 impurity of the pharmaceutical composition disclosed in the present invention can be controlled to be 0.10% or less, or even 0.05% or less after being examined at 25 ° C for 24 weeks.
  • 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)-ϋ-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" (Cancidas ) 。 卡泊芬净的稳定 性很差, 极易发生降解, 产生多种降解杂质, RRT (相对保留时间) 1.35的降 解杂质是其中主要的一种。 为了保证用药的安全, 默沙东的上市产品"科赛斯" 的质量标准中对该杂质的限度规定为不超过 0.2%。
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降解杂质 RRT (相对保留 时间) 1.35进行说明与限定。 降解杂质 RRT1.35根据 PDA (吸收光谱) 图谱可知, 其具有如图 4所示的特征吸收峰。 其与式 I化合物的特征吸收峰相类似, 式 I化合 物的特征吸收峰如图 5所示。
参考文献 US20090324635公开了一种不含杂质 A (式 II) 的卡泊芬净, 以 及制备这种卡泊芬净的方法。 参考文献 US20090291996 公开了一种不含杂质 Co (式 III ) 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 II降解杂质和 RRT 1.35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, 但未对 RRT 1.35 的杂质说明与限定。 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 的组合物在我们进行配方摸索的过程中曾经也进行过实验, 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。
Figure imgf000004_0001
Figure imgf000004_0002
( III)
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 T1.35降解杂质未进行有效的严格控制。 因此有必要开发一种新的药用组合 物及工艺,可以降低卡泊芬净的 RRT 1.35降解杂质 HPLC含量,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, 其中所述组合物中在以下 HPLC条件下相对保留时间约为 1.35的杂质的 HPLC含 量不超过 0.10% ;
Figure imgf000005_0001
在一个具体实施方式中, 所述组合物中相对保留时间约为 1 .35的杂质的 HPLC含量不超过 0.05%。
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。
在另一实施方式中, 所述 HPLC条件为:
高效液相色谱仪: WATERS 2695-2998
分析柱: YMC-Pack ODS-A柱, 规格: 250x4.6mm, S-5um, 1 .2nm
柱温: 35 °C
检测波长: 220nm
流动相: A: 0.1 %的高氯酸和 0.075 %的氯化钠溶液;
B : 乙腈;
梯度条件如下表所示:
时间 (分钟) A % B%
初始 65.5 34.5
14.5 65.5 34.5
35 50 50
45 35 65
50 20 80 52 20 80
53 65.5 34.5
66 65.5 34.5
流量为: 1.45 ml/min, 调整色谱系统, 使主峰保留时间为 20min左右。 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-rC/min的速度升至 30-40 °C;
h、 搁板温度在 30-40 °C下维持 300-960min; 和
i、 干燥结束后压塞, 出箱, 轧盖;
在另一具体的实施方式中, 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. rC/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 CancidasR1571的 HPLC图谱。
Figure imgf000008_0001
图 2是实施例中的配方 3在 25°C下 24周的 HPLC图谱。
峰名 保留时间 (分钟) %面积
卡泊芬净 20.496 99.14 RRT 1. 35杂质 27. 448 0. 08 图 3是实施例中的配方 3 在 2-8 °C下 24周的 HPLC图谱。
Figure imgf000009_0001
图 4是 RRT 1.35杂质的特征吸收峰。
图 5是式 I化合物的特征吸收峰。 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"相对保留时间 (RRT)' '是指在一定 HPLC 条件下某峰相对 于主峰的保留时间之比, 例如, 在一定 HPLC条件下, 主峰的保留时间是 1分 钟,而另一峰的保留时间是 2分钟,则后者的相对保留时间 (RRT)是 2。相应地, 本文所述 RRT 1.35的杂质是指在本文所述 HPLC条件下,相对保留时间为 1.35 的杂质。
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 0.17%面积比的 RRT 1.35降解杂质, RRT 1.35 降解杂质是卡泊芬净的热降解杂质, 其降解过程受温度的影响很大, 在卡泊芬 净的药用组合物的制备和储存过程中较易产生。
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 RRT 1.35降解杂质 HPLC含量不超过 0.10%, 更优选 RRT 1.35 降解 HPLC含量不超过 0.05%。
本发明的组合物中所述 RRT1.35降解杂质的 HPLC相对保留时间 (RRT) 为 1.32-1.37。
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。
所述氨基酸优选中性氨基酸; 更优的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; 最优的为甘氨酸。
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。 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 saline)或生理 盐水 (physiological saline),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 saline)或生理盐水 (physiological saline) ,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。 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 "-COOH"数目相等的一类氨基酸。
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 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 1 :4-1.5: 1。
本方面还提供了一种制备 RRT 1.35降解杂质不超过 0.10% (HPLC) 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 RRT 1.35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 ODS-A柱, 规格: 250x4.6mm, 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:
时间 (分钟) A% B%
初始 65.5 34.5
14.5 65.5 34.5 35 50 50
45 35 65
50 20 80
52 20 80
53 65.5 34.5
66 65.5 34.5
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 RRT1.35的峰为 lml/min流量的 RRT1.26的峰。
%相对峰面积, gp, 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: O.O lmol/L 的醋酸钠溶液 =1 : 4稀释至 0.1mg/ml, 在 5 °C下注入上述液相色谱系统。 "科赛 斯"中的 RRT 1.35杂质情况如下:
Figure imgf000013_0001
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 ρΗό.Ο 配制好的溶液按 0.5mL/瓶分装至 2mL的抗生素瓶中,用经 1 10°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 0.1 °C/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 0.1 °C/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 0.1 °C/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 0.1 °C/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 0.1 °C/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 l °C/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、 75%RH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、 60%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 )。
冻干制品分别放置于 40°C、 75%RH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、 60%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)。 实施例 1
卡泊芬净药用组合物制备
配制过程为: 先将糖类保护剂和甘氨酸 (或其他氨基酸) 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
Figure imgf000018_0001
各冻干程序如下:
冻干程序 A:
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 540min;
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 420min;
i、 搁板温度以 0.1°C/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 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 540min;
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 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. 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 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 780min;
i、 搁板温度以 0.1°C/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 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 700min;
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 660min;
i、 搁板温度以 0.1°C/min的速度升至 40°C; j、 搁板温度在 40°C下维持 600min;
k、 干燥结束后压塞, 出箱, 轧盖。
冻干程序 E:
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;
m、 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 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 RRT 1.35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 RRT 1.35杂质 /%相对峰面积 配方编号
0时 24周 0时 24周
1 99.17 97.26 0.1 1 0.25
2 99.10 96.75 0.13 0.27
3 99.27 99.14 0.01 0.08
4 99.26 99.15 0.02 0.08
5 99.25 99.17 0.02 0.13
6 99.27 99.14 0.03 0.07
7 99.24 99.17 0.02 0.10
8 99.25 99.13 0.02 0.07
9 99.27 99.15 0.02 0.09
10 99.26 99.16 0.01 0.09
1 1 99.25 99.1 1 0.01 0.13
12 99.20 98.91 0.1 1 0.23
13 99.23 99.13 0.02 0.07
14 99.25 99.10 0.02 0.08
15 99.26 99.14 0.01 0.10
16 99.23 99.13 0.02 0.10
17 99.20 99.16 0.02 0.08 18 99.25 99.12 0.01 0.07
19 99.22 99.05 0.02 0.09
20 99.24 99.09 0.02 0.08
21 99.27 99.1 1 0.02 0.10
22 99.13 97.15 0.12 0.25
2-8°C稳定性试验结果如下表所示:
W -pr έΕ¾ -& 卡泊芬净 /%相对峰面积 T 1.35杂质 /%相对峰面积
力綱
0时 24周 0时 24周
1 99.17 99.1 1 0.1 1 0.13
2 99.10 98.99 0.13 0.14
3 99.29 99.24 0.01 0.04
4 99.26 99.23 0.02 0.04
5 99.25 99.24 0.02 0.05
6 99.27 99.20 0.03 0.04
7 99.24 99.23 0.02 0.03
8 99.25 99.20 0.02 0.03
9 99.27 99.22 0.02 0.04
10 99.26 99.22 0.01 0.03
1 1 99.25 99.21 0.01 0.03
12 99.20 99.16 0.1 1 0.12
13 99.23 99.19 0.02 0.05
14 99.25 99.21 0.02 0.05
15 99.26 99.24 0.01 0.04
16 99.23 99.20 0.02 0.05
17 99.20 99.13 0.01 0.03
18 99.25 99.17 0.02 0.05
19 99.22 99.12 0.02 0.07
20 99.24 99.18 0.01 0.05
21 99.27 99.22 0.02 0.04
22 99.13 99.04 0.12 0.13 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 RRT 0.95 (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, 总杂质含量与 0时相比普遍不增反降, 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 °C 24周的稳定性考察后,其 RRT 1.35杂质都能够控制在 0.10%以下, 甚至是 0.05%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 HPLC相对保留时间约为 1.35 的杂质的 HPLC含量不超过 0.10%;
Figure imgf000025_0001
2. 如权利要求 1所述的药用组合物, 其特征在于, 所述组合物中相对保留 时间约为 1 .35的杂质的 HPLC含量不超过 0.05%。
3. 如权利要求 1或 2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。
4. 如权利要求 1或 2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。
5. 如权利要求 1或 2所述的药用组合物, 其特征在于, 所述 HPLC的条件为: 高效液相色谱仪: WATERS 2695-2998
分析柱: YMC-Pack ODS-A柱, 规格: 250x4.6mm, S-5um, 1 .2nm
柱温: 35 °C
检测波长: 220nm
流动相: A: 0. 1 %的高氯酸和 0.075 %的氯化钠溶液;
B : 乙腈;
梯度条件如下表所示:
时间 (分钟) A % B%
初始 65.5 34.5
14.5 65.5 34.5
35 50 50 45 35 65
50 20 80
52 20 80
53 65.5 34.5
66 65.5 34.5
流量为: 1.45 ml/min, 调整色谱系统, 使主峰保留时间为 20min左右。
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。
1 1. 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 6-1 1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 6-1 1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 1-15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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ES2519240B1 (es) 2015-08-19
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CN102488889A (zh) 2012-06-13
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