WO2012103802A1 - 一种含有棘白菌素类抗真菌剂米卡芬净的液体药用组合物 - Google Patents

一种含有棘白菌素类抗真菌剂米卡芬净的液体药用组合物 Download PDF

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WO2012103802A1
WO2012103802A1 PCT/CN2012/070786 CN2012070786W WO2012103802A1 WO 2012103802 A1 WO2012103802 A1 WO 2012103802A1 CN 2012070786 W CN2012070786 W CN 2012070786W WO 2012103802 A1 WO2012103802 A1 WO 2012103802A1
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pharmaceutically acceptable
micafungin
pharmaceutical composition
stabilizer
composition according
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PCT/CN2012/070786
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English (en)
French (fr)
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洪云海
薛颖
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 US13/982,874 priority Critical patent/US20130338060A1/en
Priority to JP2013552092A priority patent/JP5723031B2/ja
Publication of WO2012103802A1 publication Critical patent/WO2012103802A1/zh

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to liquid pharmaceutical compositions for treating and/or preventing fungal infections. More specifically, the present invention relates to a compound represented by the formula (I):
  • a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable amount of a stabilizer such as a monosaccharide, a disaccharide or a polysaccharide, or a combination thereof, preferably lactose, sucrose, maltose, trehalose or a combination thereof. It is a liquid composition.
  • the compound represented by the formula (I) is a cyclic polypeptide compound, that is, micafungin.
  • Mi cafungin Sodium also known as FK463, trade name: Mycamine, Fujisawa, Japan
  • Its structure is as follows. III, derived from the chemical modification of the fermentation product of the genus Coleophoma empedri t. It was first listed in Japan in 2002 and was approved for FDA approval in the US in May 2005. Its clinical trials have shown that micafungin is effective in treating Candida and Aspergillus and will be used as a first-line treatment for infections caused by Candida.
  • Patent CN1 179748C discloses a stable pharmaceutical composition of lyophilized form of micafungin which contains lactose as a stabilizer.
  • Patent CN100352495C discloses a stable pharmaceutical composition in lyophilized form of micafungin which contains maltose as a stabilizer.
  • the above compositions are not ideal, they are all freeze-dried products, the production process is relatively complicated, the energy consumption in the freeze-drying process is high, the production cycle is long, and the limited freeze-drying area of the freeze dryer directly affects the production efficiency. , increased production costs. In the course of medication, reconstitution is needed, which is not only inconvenient to operate, but also increases the risk of medication. Therefore, it is highly desirable to develop a pharmaceutical composition that is simple in production, low in energy consumption, and stable.
  • compositions provided herein provide a safe, stable, reproducible liquid formulation that can be used directly to treat/prevent fungal infections.
  • the inventors have surprisingly discovered that a pharmaceutically acceptable compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable amount of a stabilizer, such as a monosaccharide, disaccharide or polysaccharide, or a combination thereof, are included
  • a pharmaceutically acceptable compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable amount of a stabilizer, such as a monosaccharide, disaccharide or polysaccharide, or a combination thereof are included
  • the liquid pharmaceutical compositions are surprisingly stable and are even more stable than lyophilized formulations.
  • the invention provides a pharmaceutical composition comprising:
  • composition of the invention is a liquid formulation.
  • the stabilizers included in the compositions of the present invention are monosaccharides, disaccharides or polysaccharides, or compositions thereof, preferably lactose, sucrose, maltose, trehalose or combinations thereof. Its concentration is 10-500 mg/ml, preferably 20-400 mg/ml.
  • the concentration of the compound of formula I or a pharmaceutically acceptable salt thereof in the composition of the invention is from 1 to 150 mg/ml, preferably from 5 to 100 mg/ml.
  • composition of the present invention preferably comprises a weight ratio of the stabilizer to the compound of formula I or a pharmaceutically acceptable salt thereof of from 100:1 to 1:20, preferably from 20:1 to 1:5.
  • 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.
  • additional pH adjusting agents such as phosphate buffers, acetate buffers, citrate buffers and the like as pharmaceutically acceptable pH adjusting agents. 5 ⁇
  • the pH of the buffer is preferably 4-7, more preferably 4. 5-6.
  • the pharmaceutical composition of the present invention comprises, as a pharmaceutically active component, a pharmaceutically acceptable salt of a compound of formula I, a suitable pharmaceutically acceptable amount of a stabilizer, lactose.
  • the pharmaceutical composition of the invention comprises as a pharmaceutically active component
  • composition of the invention comprises as a pharmaceutically active component
  • a pharmaceutically acceptable salt of the compound I, a suitable pharmaceutically acceptable amount of the stabilizer maltose is provided.
  • the pharmaceutical composition of the invention comprises as a pharmaceutically active component
  • compositions of the present invention may further comprise, for example, one or more pharmaceutically acceptable stabilizers, including diluents or carriers well known in the art, which are suitable for compositions intended for parenteral administration.
  • stabilizers such as for intramuscular, subcutaneous, intravenous, intraperitoneal or intramuscular administration.
  • Such stabilizers may include, for example, antioxidants, skin extenders, preservatives, carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • 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.
  • micafungin and its pharmaceutically acceptable salts as used herein are described in U.S. Patent 6,774,104 B1.
  • the pharmaceutically acceptable salt of micafungin is preferably micafungin sodium salt.
  • Figure 1 is an HPLC chromatogram of Formulation 1 at 70 °C for 0 days in the examples.
  • Figure 2 is an HPLC chromatogram of Formulation 1 at 70 °C for 4 weeks in the examples.
  • Figure 3 is an HPLC chromatogram of Formulation 6 at 70 °C for 0 days in the examples.
  • Figure 4 is a HPLC chromatogram of Formulation 6 at 70 °C for 4 weeks in the examples. detailed description
  • the analytical column used was YMC-Pack 0DS-A column, specification: 250 X 4. 6mm, S-5um, 1. 2nm, column temperature: 35 °C, 210nm detection.
  • nitrile-phosphate buffer pH 3.0 [take sodium dihydrogen phosphate 16.56g and sodium perchlorate 7. 73g, dissolve with water and dilute to 1000ml, adjust pH3 with dilute phosphoric acid (1 ⁇ 10) . 0] ( 45 : 70 ).
  • the content of micafungin was calculated according to the external standard method.
  • the raw materials used in the examples were all produced by Shanghai Tianwei Bio-Pharmaceutical Co., Ltd. Comparative example 1
  • the lactose was dissolved in pure water (200 ml) under heating at less than 50 °C. After cooling to below 20 °C, add micafungin sodium to the lactose solution to avoid air bubbles with gentle agitation. After adding 2% aqueous citric acid solution (0.95 ml), a 0.4% aqueous sodium hydroxide solution (about 2.4 ml) was added to the solution to adjust pH 5.5, and then diluted with pure water to give a given volume (250 ml). The resulting solution was dispensed into 100 10 ml volume vials, 2.5 ml each vial. The solution in each vial was lyophilized by a conventional method using a lyophilizer (Virtis Genesis 25ES). To obtain lyophilized compositions each containing 25 mg of micafungin sodium.
  • a lyophilized composition (Formulation 2) each containing 25 mg of micafungin sodium was prepared according to Comparative Example 1, except that 15 g of maltose was used instead of lactose.
  • Example 4 Glacial acetic acid 1.5mg/ml The sodium hydroxide was adjusted to pH 5. 5 The prepared solution was dispensed into a 10 mL vial according to 2.5 mL/bottle, and the whole was stoppered and rolled. The obtained liquid product was subjected to the same stability test as in Comparative Example 1.
  • Example 4 Glacial acetic acid 1.5mg/ml The sodium hydroxide was adjusted to pH 5. 5 The prepared solution was dispensed into a 10 mL vial according to 2.5 mL/bottle, and the whole was stoppered and rolled. The obtained liquid product was subjected to the same stability test as in Comparative Example 1. Example 4
  • the formulation process is similar to that of Example 3, except that during the formulation process, the stabilizer is selected between trehalose, sucrose, lactose or maltose, and the pH adjuster used is selected between acetate, phosphate or citrate. , even without any additional pH adjuster, resulting in different formulations, the composition of each composition is as follows:
  • the liquid formulation with trehalose, sucrose, lactose or maltose or a combination thereof as a stabilizer, and the weight ratio of the stabilizer to micafungin sodium is 100:1-1:20, preferably 20: In the case of 1-1:5, it has good stability.
  • the HPLC analysis of Formulations 1 and 6 is shown in Figures 1-4.

Description

种含有棘白菌素类抗真菌剂米卡芬净的液体药用组合物
技术领域
本发明涉及治疗和 /或预防真菌感染的液体药用组合物。 更具体地说， 本发明涉及式 （I ) 表示的化合物：
Figure imgf000002_0001
或其药学上可接受的盐， 以及药学上可接受量的稳定剂， 如单糖， 二糖 或多糖， 或其组合物， 优选乳糖、 蔗糖、 麦芽糖、 海藻糖或其组合物。 其为 液体组合物。 背景技术
由式 （I ) 表示的化合物为环状多肽化合物， 即米卡芬净。 米卡芬净钠 (Mi cafungin Sodium , 又称 FK463 , 商品名： Mycamine , 日本藤泽公司）是继 卡泊芬净之后 FDA批准的第二种棘白菌素类抗真菌药物， 其结构如式 I I I， 由鞘茎点霉 Coleophoma empedri t发酵产物经化学修饰衍生而得。 其于 2002 年首次在日本上市， 并于 2005年 5 月通过 FDA批准在美国上市。 其临床试 验表明， 米卡芬净对于治疗念珠菌属及曲霉菌属很有效， 并将作为治疗由念 珠菌感染引起的一线药物。
由于米卡芬净及其盐一般对光、 热、 湿度、 酸等不稳定， 因此需要开发 稳定该化合物及其盐的药用组合物。 专利 CN1 179748C 披露了米卡芬净的冻 干形式的稳定的药用组合物， 其含有乳糖作为稳定剂。 专利 CN100352495C 披露了米卡芬净的冻干形式的稳定的药用组合物， 其含有麦芽糖作为稳定 剂。 然而上述组合物并不是最理想， 其都为冻干制品， 其制作过程较为复杂， 冻干过程能耗较高， 生产周期长， 冻干机有限的冻干面积等因素都直接影响 了生产效率， 增加了生产成本。 且在用药过程中， 需要复溶， 不但操作不方 便， 而且增加了用药的风险。 因此， 非常有必要开发出一种制作过程简单， 能耗低且稳定的药用组合物。
本发明提供的组合物提供了一种安全， 稳定， 可复制的液体制剂， 可直 接用于治疗 /预防真菌感染。 发明内容
本发明人令人意外的发现包含药学上可接受的式 （I ) 化合物或其药学 上可接受的盐和药学上可接受量的稳定剂， 如单糖、 二糖或多糖， 或其组合 物的液体药用组合物令人意外的稳定， 其稳定性甚至优于冻干制剂。
本发明提供了药物组合物， 其包含：
a) 式 I所示棘白菌素类抗真菌化合物或其药学上可接受的盐， 和 b) 药学上可接受量的稳定剂。 本发明所述组合物为液体制剂。
本发明所述组合物中包含的稳定剂是单糖、 二糖或多糖， 或其组合物， 优选为乳糖、 蔗糖、 麦芽糖、 海藻糖或其组合物。 其浓度为 10-500mg/ml， 优选 20- 400mg/ml。
本发明所述组合物中式 I 化合物或其药学上可接受的盐的浓度为 1- 150mg/ml， 优选 5- 100mg/ml。
本发明的组合物优选包含稳定剂与式 I化合物或其药学上可接受的盐的 重量比为 100 : 1- 1 : 20， 优选 20 : 1-1 : 5。
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 4-7， 更优选 4. 5-6. 5。
在一个实施方案中， 本发明的药物组合物包含作为药物活性组分的式 I 化合物的药学上可接受的盐、 合适的药学上可接受量的稳定剂乳糖。
在另一个实施方案中， 本发明的药物组合物包含作为药物活性组分的式
I化合物的药学上可接受的盐、 合适的药学上可接受量的稳定剂蔗糖。 在另一个实施方案中， 本发明的药物组合物包含作为药物活性组分的式
I化合物的药学上可接受的盐、 合适的药学上可接受量的稳定剂麦芽糖。
在另一个实施方案中， 本发明的药物组合物包含作为药物活性组分的式
I化合物的药学上可接受的盐、 合适的药学上可接受量的稳定剂海藻糖。
本发明的组合物还可以进一步包含另一种， 例如一种或多种药学上可接 受的稳定剂， 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 射制剂。 这类稳定剂可以包括， 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。
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。
本文所用的术语 "米卡芬净"和其药学上可接受的盐描述在 US6774104B1 中。 米卡芬净药学上可接受的盐优选为米卡芬净钠盐。 附图说明
图 1是实施例中配方 1在 70 °C下 0天的 HPLC图谱。
图 2是实施例中配方 1在 70 °C下 4周的 HPLC图谱。
图 3是实施例中配方 6在 70 °C下 0天的 HPLC图谱。
图 4是实施例中配方 6在 70 °C下 4周的 HPLC图谱。 具体实施方式
米卡芬净 HPLC分析方法：
所用分析柱为 YMC- Pack 0DS- A柱， 规格： 250 X 4. 6mm， S- 5um， 1. 2nm， 柱温： 35 °C， 210nm检测。
流动相： 已腈-磷酸盐缓冲液 （PH3. 0 ) [取磷酸二氢钠 16. 56g和高氯酸 钠 7. 73g，加水溶解并稀释到 1000ml，用稀磷酸（1→10 )调 pH3. 0] ( 45 : 70 )。
按外标法计算米卡芬净的含量。 实施例所用的原料均产自于上海天伟生物制药有限公司。 对比例 1
米卡芬净冻干制剂制备
按照专利 CN100352495C的实施例 1进行组合物的制备。 配方 1如下： 米卡芬净钠 2.5g
乳糖 20g
无水柠檬酸适量
氢氧化钠适量
将乳糖在低于 50°C加热下溶于纯水（200ml)。 冷却至 20°C以下后， 向 乳糖溶液中加入米卡芬净钠， 在温和搅拌下避免产生气泡。 在加入 2%柠檬酸 水溶液（0.95ml)后， 向溶液中加入 0.4%氢氧化钠水溶液（约 2.4 ml)， 以调 节 pH5.5，然后用纯水稀释， 产生给定的体积（250ml)。 将所得的溶液分装到 100个 10 ml 体积的管形瓶中， 每个管形瓶 2.5ml. 用常规方法， 用冻干机 (Virtis Genesis 25ES)将各个管形瓶中的溶液冻干， 以获得各含 25mg米卡 芬净钠的冻干组合物.
所得的冻干制品保存在 70°C下， 4周后进行米卡芬净残留量分析。 对比例 2
米卡芬净冻干制剂制备
按照对比例 1制备各含 25mg的米卡芬净钠的冻干组合物 （配方 2) ， 只 是用 15g麦芽糖代替乳糖。
所得的冻干制品与对比例 1进行相同的稳定性考察。 实施例 3
米卡芬净液体制剂制备
取 30ml水， 加入 75 μ ΐ 的冰醋酸， 用 1M的氢氧化钠调至 ρΗ5.5。 取海 藻糖 12.0g溶于该缓冲溶液中， 再加入米卡芬净钠 1.25g， 轻轻搅拌溶解， 加水定容到 50mL， 0.22μηι膜过滤， 组合物 （配方 3) 的组成如下表：
米卡芬净钠 25mg/ml
海藻糖 240mg/ml
冰醋酸 1.5mg/ml 氢氧化钠 调至 pH5. 5 配制好的溶液按 2. 5mL/瓶分装至 10mL 的管形瓶中， 全加塞， 轧盖。 所 得的液体制品与对比例 1进行相同的稳定性考察。 实施例 4
米卡芬净液体制剂制备
配制过程与实施例 3相似，所不同的是在配制过程中， 稳定剂在海藻糖、 蔗糖、 乳糖或麦芽糖之间选择， 所用 pH 调节剂在醋酸盐、 磷酸盐或柠檬酸 盐之间选择， 甚至是不加任何额外的 pH 调节剂， 由此得到不同的配方， 各 组合物配方的组成如下表：
Figure imgf000006_0001
各个配方的组合物， 同样进行对比例 1 中所述的稳定性考察。 实施例 5
米卡芬净液体制剂制备
对比例 1、 对比例 2、 实施例 3和实施例 4 的样品分别进行稳定性考察 后， 用 HPLC对活性物质进行分析。 70°C稳定性考察 4周的结果如下表所示:
Figure imgf000007_0001
从上表可以看出， 以海藻糖、 蔗糖、 乳糖或麦芽糖或其组合物为稳定剂 的液体配方， 且稳定剂与米卡芬净钠重量比为 100:1-1:20， 优选 20:1-1:5 的情况下， 其具有良好的稳定性。 配方 1和 6的 HPLC分析图谱见附图 1-4。

Claims

权 利 要 求
1.用于抗真菌的药用组合物， 其特征在于， 所述的组合物包含:
a ) 药用有效量的式 I化合物或其药学上可接受的盐； 和
b ) 药学上可接受量的稳定剂；
Figure imgf000008_0001
2. 如权利要求 1所述的药用组合物， 其特征在于， 其中所述的式 I化合物 药学上可接受的盐优选为钠盐。
3.如权利要求 1所述的药用组合物， 其特征在于， 其中所述的稳定剂选 自： 单糖、 二糖或多糖， 或其组合物； 优选自： 乳糖、 蔗糖、 麦芽糖、 海藻 糖、 或其组合。
4. 如权利要求 1-3 任一所述的药用组合物， 其特征在于， 所述的组合 物为液体制剂。
5.如权利要求 1所述的药用组合物，其特征在于，组合物中含有 l-150mg/ml 的式 I化合物或其药学上可接受的盐。
6. 如权利要求 5所述的药用组合物，其特征在于，组合物中含有 5-100mg/ml 的式 I化合物或其药学上可接受的盐。
7. 如权利要求 1 所述的药用组合物， 其特征在于， 组合物中含有 10-500mg/ml的稳定剂。
8 . 如权利要求 7 所述的药用组合物， 其特征在于， 组合物中含有 20-400mg/ml的稳定剂。
9. 如权利要求 1 -8 任一所述的药用组合物的用途， 其特征在于， 用于 制备预防和 /或治疗哺乳动物真菌感染药物。
PCT/CN2012/070786 2011-01-31 2012-01-31 一种含有棘白菌素类抗真菌剂米卡芬净的液体药用组合物 WO2012103802A1 (zh)

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JP7109189B2 (ja) * 2014-05-29 2022-07-29 シャンハイ テックウェル バイオファーマシューティカル カンパニー リミテッド シクロペプチド系化合物の組成物およびその製造方法と使用
WO2017047299A1 (ja) * 2015-09-15 2017-03-23 富士フイルム株式会社 注射用液剤組成物
KR101880179B1 (ko) * 2016-11-03 2018-07-20 한국생명공학연구원 미카펀진(micafungin) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 항바이러스용 약학적 조성물
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