WO2020077564A1 - 一种稀释稳定性好的替尼泊苷注射用溶液及其制备方法 - Google Patents

一种稀释稳定性好的替尼泊苷注射用溶液及其制备方法 Download PDF

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WO2020077564A1
WO2020077564A1 PCT/CN2018/110655 CN2018110655W WO2020077564A1 WO 2020077564 A1 WO2020077564 A1 WO 2020077564A1 CN 2018110655 W CN2018110655 W CN 2018110655W WO 2020077564 A1 WO2020077564 A1 WO 2020077564A1
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teniposide
injection
cyclodextrin
preparation
aqueous phase
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PCT/CN2018/110655
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English (en)
French (fr)
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王刚
董祥玉
赵研博
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南京远航生物科技有限公司
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Priority to JP2021521150A priority Critical patent/JP7267640B2/ja
Priority to EP18936998.6A priority patent/EP3868363A4/en
Priority to PCT/CN2018/110655 priority patent/WO2020077564A1/zh
Priority to US17/284,430 priority patent/US20210338702A1/en
Publication of WO2020077564A1 publication Critical patent/WO2020077564A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a solution for teniposide injection with good dilution stability and a preparation method thereof.
  • Teniposide (Teniposide, Vumon, VM-26) Alias: Weimeng, Vie 26, foot leaf poison thiomethylene glucoside, Banglai, podophyllotoxin, is a semipodoposide Synthetic derivatives belong to antitumor drugs of plant origin. It is a cycle-specific cytotoxic drug that inhibits DNA topoisomerase II, causing double-strand or single-strand destruction to stop cell mitosis at the late S or early G2 stage, thereby hindering tumor cell division and inhibiting tumor growth.
  • Teniposide has a significant therapeutic effect, its biological activity is 5 to 10 times that of the same type of drug etoposide, and clinical data show that teniposide has fewer side effects, less toxicity, and no significant effect on liver and kidney functions. Because of its broad-spectrum antitumor activity, teniposide is usually used in combination with other anticancer drugs in clinical practice: mainly used for malignant lymphoma, Hodgkin's disease, acute lymphocytic leukemia, glioblastoma, Vascular tumor, astrocytoma, bladder cancer, neuroblastoma, and other solid tumors in children.
  • each ampoule contains 50mg of teniposide, 150mg of benzyl alcohol, 300mg of N, N-dimethylacetamide, 2.5g of polyoxyethylene castor oil (Cremophor EL), 42.7% (v / v) absolute ethanol.
  • each ampoule contains 50mg of teniposide, 150mg of benzyl alcohol, 300mg of N, N-dimethylacetamide, 2.5g of polyoxyethylene castor oil (Cremophor EL), 42.7% (v / v) absolute ethanol.
  • it is administered at a body surface area of 50 to 100 mg / m2, diluted with 5% glucose solution or physiological saline, and then instilled.
  • the problems in the clinical use of commercially available preparations are mainly that the prescription contains a large amount of polyoxyethylene castor oil. After use, it can cause the release of histamine in the body and cause serious allergic reactions. These allergic reactions include bronchospasm, shortness of breath, fatigue, and low blood pressure. To this end, the doctor must understand the patient's allergy history before the doctor's order, such as whether they are allergic to teniposide or castor oil; during clinical use, medical staff should closely observe the patient's condition and use antihistamine drugs to reduce The severe allergic reaction caused by polyoxyethylene castor oil leads to a very inconvenient clinical application, causing great pain to the patient and poor compliance.
  • the polyoxyethylene castor oil will leaching the plasticizer diethyl phthalate when it comes into contact with containers, injections, and infusion bags made of polyvinyl chloride plastic, resulting in toxic reactions.
  • the benzyl alcohol contained in the commercially available injection may cause damage to the newborn, and is prohibited for intramuscular injection in children.
  • the commercially available injections have poor stability when diluted, and crystals are often precipitated to form fine precipitates that block local blood vessels of patients.
  • the teniposide solution with a concentration of 1 mg / mL must be used within 4 hours when stored at room temperature and under ordinary day-off lights to reduce the possibility of precipitation.
  • the diluted injection solution often also exhibits precipitation during the long-term instillation, and the precipitation status needs to be observed from time to time during the infusion.
  • the purpose of the present invention is to provide a solution for teniposide injection with good dilution stability and low irritation of organic solvents.
  • Another object of the present invention is to provide a method for preparing the teniposide injection solution.
  • a teniposide composition is composed of teniposide and cyclodextrin.
  • the mass ratio of teniposide: cyclodextrin is 1: 5-20; preferably 1: 10-15; further preferably 1:12.
  • the cyclodextrin is preferably selected from one or more of hydroxypropyl- ⁇ -cyclodextrin, sulfobutyl- ⁇ -cyclodextrin, and hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin; preferably Sulfobutyl- ⁇ -cyclodextrin.
  • a solution or powder injection for teniposide injection in addition to the teniposide composition of the present invention, also contains a stabilizer and an additional agent.
  • the stabilizer is preferably selected from any one or more of polyvinylpyrrolidone, polyvinyl alcohol, sodium dodecyl sulfonate, sodium dodecyl sulfate, poloxamer, and polyethylene glycol; tinib
  • the mass ratio of podoside to stabilizer is 1: 20-100, further preferably 1: 20-80, still more preferably 1: 40-50.
  • the additional agent is selected from any one or more of osmotic pressure adjusting agent, pH value adjusting agent, metal ion complexing agent and antioxidant;
  • the osmotic pressure adjusting agent is selected from propylene glycol, glycerin and mannitol Any one or more of the above;
  • the pH adjusting agent is selected from any one of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, sorbic acid, lipoic acid, sodium hydroxide, sodium bicarbonate, glycine, sodium dihydrogen phosphate
  • the metal ion complexing agent is selected from any one or more of ethylenediaminetetraacetic acid, sodium salt of ethylenediaminetetraacetic acid, potassium salt of ethylenediaminetetraacetic acid;
  • the antioxidant is selected From any one or more of sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, and vitamin C; the mass ratio of tenipos
  • the solution or powder for injection of teniposide preferably further contains the following components: teniposide, cyclodextrin, stabilizer, additives and water for injection; wherein the mass ratio of teniposide to cyclodextrin It is 1: 5-20; the mass ratio of teniposide to stabilizer is 1: 20-100; the mass ratio of teniposide to additives is 1: 1-10.
  • the solution for teniposide injection is preferably prepared mainly through the following steps:
  • step 3 After thoroughly mixing the organic phase obtained in step 2) and the aqueous phase obtained in step 1), the organic solvent is removed, and the volume of water for injection is adjusted to obtain the teniposide composition.
  • the organic solvent is preferably selected from any one or more of acetone, methanol, ethanol or chloroform.
  • the preparation method of the teniposide injection solution of the present invention includes the following steps:
  • cyclodextrin Dissolve cyclodextrin, stabilizer and additives in water for injection as the aqueous phase, wherein cyclodextrin is 5% -35% (g / 100mL) of the final volume, preferably 15% -35%;
  • step 3 After thoroughly mixing the organic phase obtained in step 2) with the aqueous phase obtained in step 1) in a volume ratio of 1: 1.5 to 1.8, the organic solvent is removed and the volume of water for injection is adjusted to obtain the teniposide composition.
  • the organic solvent is preferably acetone, methanol, ethanol or chloroform.
  • the step of removing the organic solvent is as follows: at room temperature, the organic phase is added to the aqueous phase while stirring, after stirring for 0.5 hours, stirring is continued for 2 hours under low negative pressure, and stirring is continued for 1 hour under high vacuum;
  • the low negative pressure condition is -0.01 to -0.03Mpa, and the pressure in the high vacuum state is -0.1Mpa.
  • the teniposide composition in the present invention avoids the use of auxiliary materials such as benzyl alcohol, dimethylacetamide and polyoxyethylene castor oil, which have greater side effects, can predictably reduce the side effects caused by the auxiliary materials, and improve the patient's compliance.
  • auxiliary materials such as benzyl alcohol, dimethylacetamide and polyoxyethylene castor oil
  • the imitated commercial preparations need to be operated gently. Too much injection of the injection solution into the dilution solvent will increase the possibility of crystallization. The risk of impact, to facilitate the use of medical personnel.
  • the teniposide composition of the present invention successfully solves the drawbacks of the commercially available teniposide injection that is very easy to precipitate out and form a precipitate during dilution, reduces the risk of infusion needle or blood vessel blockage, and is convenient for clinical use.
  • the present invention improves the defect that the product is unstable during the dilution process.
  • 600 mg of sulfobutyl- ⁇ -cyclodextrin, 2000 mg of PEG300, 60 mg of PVP k12, and 60 mg of citric acid were dissolved in 3 mL of water for injection to prepare an aqueous phase.
  • 600 mg of sulfobutyl- ⁇ -cyclodextrin, 2000 mg of PEG400, 80 mg of PVP k17, and 60 mg of lipoic acid were dissolved in 3 mL of water for injection to prepare an aqueous phase.
  • 600 mg of sulfobutyl- ⁇ -cyclodextrin, 2400 mg of PEG400, 60 mg of PVP k30, and 60 mg of glycine were dissolved in 3 mL of water for injection to prepare an aqueous phase.
  • 500mg sulfobutyl- ⁇ -cyclodextrin, 2400mg PEG400, 100mg PVP k30, 25mg glycine were dissolved in 3mL water for injection to prepare an aqueous phase.
  • Comparative Example 1 Prepare Comparative Example 1 according to the prescription of commercially available teniposide injection. Take 50 mg teniposide, 300 mg N, N dimethylacetamide, 150 mg benzyl alcohol, 2500 mg polyoxyethylated castor oil, adjust the pH to about 5 Appropriate amounts of maleic acid and 42.7% (v / v, based on the total volume of the formulation as the basis, the same below) of absolute ethanol, evenly stirred as a commercially available control group for comparison of dilution stability.
  • 600 mg of sulfobutyl- ⁇ -cyclodextrin, 2000 mg of PEG300, 60 mg of PVP k12, and 60 mg of citric acid were dissolved in 3 mL of water for injection to prepare an aqueous phase.
  • the organic phase was added to the aqueous phase with stirring. After fully stirred for 3 hours, the mixture was stirred in a high vacuum state (approximately -0.1 Mpa) for 1 hour. The volume of water for injection was adjusted to 5 mL to obtain the teniposide composition. The resulting teniposide mixture is sealed and stored at 4 ° C, and can be used directly as an intravenous injection, or added to a 5% glucose solution or physiological saline for intravenous infusion.
  • Comparative examples 2, 5, 6, 7, and 8 have the phenomenon of precipitation of the main drug during storage. Comparative examples 3 and 4 cannot prepare an ideal aqueous solution for injection. The experimental examples of this effect are for examples 1 to 8 and comparative examples 1, 8.
  • the prepared teniposide composition was subjected to a dilution stability experiment. The experiment recorded that the teniposide composition was diluted to 50 mL, 100 mL, 250 mL, and 500 mL with physiological saline or 5% glucose solution, and each dilution volume was prepared in 6 portions. Settling at room temperature and natural light for 0.5 hour and 12 hours. Record the number of samples with precipitation.
  • the teniposide composition in the present invention avoids the use of auxiliary materials such as benzyl alcohol, dimethylacetamide and polyoxyethylene castor oil, which have greater side effects, can predictably reduce the side effects caused by the auxiliary materials, and improve the patient's compliance.
  • auxiliary materials such as benzyl alcohol, dimethylacetamide and polyoxyethylene castor oil
  • the imitated commercial preparations need to be operated gently. Too much injection of the injection into the dilution solvent will increase the possibility of crystallization.
  • the preparation of the present invention does not have this defect, which reduces the final infusion quality of the liquid preparation. The risk of impact, to facilitate the use of medical personnel.
  • the teniposide composition of the present invention successfully solves the drawbacks of the commercially available teniposide injection that is very easy to precipitate out and form a precipitate during dilution, reduces the risk of infusion needle or blood vessel blockage, and is convenient for clinical use.
  • the present invention improves the defect that the product is unstable during the dilution process.

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Abstract

本发明公开了一种稀释稳定性好的一种替尼泊苷注射用溶液及其制备方法。一种替尼泊苷注射用溶液或粉针，包含替尼泊苷、环糊精，稳定剂和附加剂；其中替尼泊苷：环糊精质量比为1：5-20。与市售替尼泊苷注射液(VUMON)相比，本发明的替尼泊制剂不含聚氧乙烯蓖麻油、苯甲酸和N,N-二甲基乙酰胺，毒副作用小，降低了病人的不良反应，病人顺应性好。本发明的替尼泊苷制剂具有极佳的稀释稳定性，稀释过程中不出现稀释或沉淀，稀释至终浓度可稳定存放12小时不析出，制备工艺简单，成本低。

Description

一种稀释稳定性好的替尼泊苷注射用溶液及其制备方法 技术领域
本发明属于药物制剂技术领域，具体涉及一种稀释稳定性好的一种替尼泊苷注射用溶液及其制备方法。
背景技术
替尼泊苷(Teniposide，Vumon，VM-26)别名：威猛、维埃坶26、足叶毒硫花亚甲基葡萄糖苷、邦莱、鬼臼噻吩苷，是一种鬼臼毒素的半合成衍生物，属于植物来源的抗肿瘤药物。它是周期特异性细胞毒药物，抑制DNA拓扑异构酶Ⅱ，导致双链或单链破坏使细胞有丝分裂停止于S晚期或G 2前期，从而阻碍肿瘤细胞分裂，抑制肿瘤生长。替尼泊苷疗效显著，其生物活性是同类型药物依托泊苷的5～10倍，且临床资料表明替尼泊苷副作用少，毒性小，对肝、肾功能无明显影响。由于替尼泊苷具有较广谱的抗肿瘤活性，临床上通常与其它抗癌药物联合应用：主要用于恶性淋巴瘤、霍奇金氏病、急性淋巴细胞性白血病、胶质母细胞瘤、空管膜瘤、星形细胞瘤、膀胱癌、神经母细胞瘤和儿童的其它实体瘤。也用于治疗小细胞肺癌、卵巢癌、乳腺癌、多发性骨髓瘤、非小细胞肺癌等；更因其中性亲脂特性，能通过血脑屏障，目前已成为临床治疗脑瘤的首选化疗药物之一。1992年替尼泊苷注射液被美国FDA正式批准用于小儿急性淋巴细胞白血病化疗，商品名为VUMON(卫萌)。我国在21世纪初仿制成功，其商品名为邦莱。
由于替尼泊苷本身几乎不溶于水，必须溶于有机溶媒溶解，而且要加入表面活性剂来增溶。市售制剂的处方组成为：每支安瓿(5ml)含替尼泊苷50mg，苯甲醇150mg，N，N-二甲基乙酰胺300mg，聚氧乙烯蓖麻油(Cremophor EL)2.5g，42.7％(v/v)的无水乙醇。临床单独使用时按体表面积50～100mg/m2给药，用5％的葡萄糖溶液或生理盐水稀释后静滴。市售制剂在临床使用过程中存在的问题主要是处方中含有大量的聚氧乙烯蓖麻油，使用后可引起体内组胺释放，而引起严重的过敏反应。这些过敏反应包括支气管痉挛、呼吸急促、疲倦、低血压等。为此，医生在医嘱前必须了解病人的过敏史，如是否对替尼泊苷或蓖麻油等过敏；在临床使用时，医务人员需密切观察病人的情况，必要时使用抗组胺药物以减轻聚氧乙烯蓖麻油造成的严重过敏反应，从而导致临床上应用起来非常不方便，给病人带来很大的痛苦，顺应性差。而聚氧乙烯蓖麻油在接触聚氯乙烯塑料制成的容器、注射剂、输液袋时会浸出增塑剂邻苯 二甲酸二乙酯，导致毒性反应。市售注射剂中含有的苯甲醇可能造成新生儿的损害，禁止用于儿童肌肉注射。市售注射剂在稀释时稳定性差，往往会析出晶体，形成细小沉淀，堵塞病人局部血管。浓度为1mg/mL的替尼泊苷溶液，贮存于室温和普通日关灯下必须要4h内使用完，以减小沉淀发生的可能性。稀释后的注射液在长时间滴注过程中也常常出现沉淀现象，滴注过程中需要不时观察沉淀状况。
近年来，国内外药学工作者致力于研究减少或替代聚氧乙烯蓖麻油，使用的新型给药系统，以提高药物疗效，降低毒副作用。如用于全身给药的脂质体、磷脂复合物、含吐温的药物组合物、乳剂，供局部给药的微球制剂和凝胶制剂，供口服给药的微乳制剂等。但这些新的给药系统还是存在诸如使用表面活性剂(聚氧乙烯蓖麻油或吐温80)的毒性、成本高、制备工艺复杂等问题。
发明内容
本发明的目的在于提供一种稀释稳定性好，有机溶剂刺激性小的替尼泊苷注射用溶液。
本发明的另一目的在于提供该替尼泊苷注射用溶液的制备方法。
本发明的目的可通过以下技术方案实现：
一种替尼泊苷组合物，由替尼泊苷和环糊精组成，替尼泊苷：环糊精质量比为1：5-20；优选1:10-15；进一步优选1:12。
所述的环糊精优选自羟丙基-β-环糊精、磺丁基-β-环糊精、羟丙基-磺丁基-β-环糊精中的一种或多种；优选磺丁基-β-环糊精。
本发明所述的替尼泊苷组合物在制备替尼泊苷注射用溶液或粉针中的应用。
一种替尼泊苷注射用溶液或粉针，除包含本发明所述的替尼泊苷组合物外，还包含稳定剂和附加剂。
所述的稳定剂优选自聚乙烯吡咯烷酮、聚乙烯醇、十二烷基磺酸钠、十二烷基硫酸钠、泊洛沙姆、聚乙二醇中的任意一种或多种；替尼泊苷与稳定剂的质量比为1：20-100，进一步优选1：20-80，更进一步优选1:40-50。
所述附加剂选自渗透压调节剂、pH值调节剂、金属离子络合剂、抗氧剂中的任意一种或多种；所述渗透压调节剂选自丙二醇、丙三醇、甘露醇中的任意一种或多种；所述pH值调节剂选自盐酸、硫酸、磷酸、柠檬酸、山梨酸、硫辛酸、氢氧化钠、碳酸氢钠、甘氨酸、磷酸二 氢钠中的任意一种或多种；所述金属离子络合剂选自乙二胺四乙酸、乙二胺四乙酸钠盐、乙二胺四乙酸钾盐中的任意一种或多种；所述抗氧剂选自亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代硫酸钠、维生素C中的任意一种或多种；替尼泊苷与附加剂的质量比为1：1-10，进一步优选1:1-5。
所述的替尼泊苷注射用溶液或粉针进一步优选主要包含以下组分：替尼泊苷、环糊精、稳定剂、附加剂及注射用水；其中替尼泊苷：环糊精质量比为1：5～20；替尼泊苷与稳定剂的质量比为1：20～100；替尼泊苷与附加剂的质量比为1：1～10。
所述的替尼泊苷注射用溶液优选主要通过下列步骤制备得到：
1)取环糊精、稳定剂和附加剂溶于注射用水为水相,其中环糊精在水相中的重浓度为终体积的5％-35％(g/100mL)，优选15％～35％；
2)取替尼泊苷，溶于有机相中,替尼泊苷在有机相中的终浓度为0.5％-1％(g/100mL)；
3)将步骤2)所得有机相与步骤1)所得水相充分混合后，除去有机溶剂，注射用水定容，即得替尼泊苷组合物。
所述有机溶剂优选自丙酮、甲醇、乙醇或氯仿中的任意一种或多种。
本发明所述的替尼泊苷注射用溶液的制备方法，包括下列步骤：
1)取环糊精、稳定剂和附加剂溶于注射用水为水相，其中环糊精为终体积的5％-35％(g/100mL)，优选15％～35％；
2)取替尼泊苷，溶于有机相中,替尼泊苷占有机相的0.5％-1％(g/100mL)；
3)将步骤2)所得有机相与步骤1)所得水相按照1:1.5-1.8体积比充分混合后，除去有机溶剂，注射用水定容，即得替尼泊苷组合物。
所述有机溶剂优选丙酮、甲醇、乙醇或氯仿。
所述除去有机溶剂的步骤为：在室温下，边搅拌边将有机相加入水相，充分搅拌0.5小时后，低负压下继续搅拌2小时后，高真空状态继续搅拌1小时；所述的低负压条件为-0.01～-0.03Mpa，所述的高真空状态的压力为-0.1Mpa。
有益效果：
本发明中的替尼泊苷组合物避免了使用副作用较大的苯甲醇、二甲基乙酰胺和聚氧乙烯蓖麻油等辅料，可预见的降低辅料引起的副作用，提高患者使用顺应度。
在稀释过程中，仿市售制剂需操作轻柔，过于剧烈的将注射液注入稀释溶剂中会加大结晶析出的可能性，本发明制剂不存在此项缺陷，降低了药液配制对最终输液质量造成影响的风险，方便医护人员的使用。
本发明中的替尼泊苷组合物成功解决了市售替尼泊苷注射液在稀释过程中极易析出、形成沉淀的弊端，降低了输注针头或血管堵塞的风险，方便临床使用。
本发明通过对减压抽离有机溶剂的过程进行优化，改善了产品在稀释过程中不稳定的缺陷。
具体实施方式
实施例1
取600mg磺丁基-β-环糊精、2000mg的PEG300、60mg的PVP k12、60mg的柠檬酸溶解于3mL的注射用水中制备为水相。
取50mg替尼泊苷加2.5mL乙醇和2.5mL丙酮溶解，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌0.5小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，注射用水定容至5mL，即得替尼泊苷注射剂制剂。所得替尼泊苷注射剂制剂置于4℃条件下密封保存，可直接作为静脉注射剂使用，或者加入到5％葡萄糖溶液或者生理盐水中供静脉滴注使用。
实施例2
取1000mg磺丁基-β-环糊精、1700mg的PEG400、60mg的泊洛沙姆、60mg的甘氨酸溶解于3mL的注射用水中制备为水相。
取50mg替尼泊苷加5mL乙醇，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌0.5小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，注射用水定容至5mL，即得替尼泊苷注射剂制剂。所得替尼泊苷注射剂制剂置于4℃条件下密封保存，可直接作为静脉注射剂使用，或者加入到5％葡萄糖溶液或者生理盐水中供静脉滴注使用。
实施例3
取600mg磺丁基-β-环糊精、2000mg的PEG400、80mg的PVP k17、60mg的硫辛酸溶解于3mL的注射用水中制备为水相。
取50mg替尼泊苷加5mL乙醇，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌0.5小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，注射用水定容至5mL，即得替尼泊苷注射剂制剂。所得替尼泊苷注射剂制剂置于4℃条件下密封保存，可直接作为静脉注射剂使用，或者加入到5％葡萄糖溶液或者生理盐水中供静脉滴注使用。
实施例4
取800mg磺丁基-β-环糊精、2000mg的PEG400、100mg的PVP k30、80mg的硫辛酸溶解于3mL的注射用水中制备为水相。
取50mg替尼泊苷加5mL丙酮，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌0.5小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，注射用水定容至5mL，即得替尼泊苷注射剂制剂。所得替尼泊苷注射剂制剂置于4℃条件下密封保存，可直接作为静脉注射剂使用，或者加入到5％葡萄糖溶液或者生理盐水中供静脉滴注使用。
实施例5
取600mg磺丁基-β-环糊精、2400mg的PEG400、60mg的PVP k30、60mg的甘氨酸溶解于3mL的注射用水中制备为水相。
取50mg替尼泊苷加5mL丙酮，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌0.5小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，注射用水定容至5mL，即得替尼泊苷注射剂制剂。所得替尼泊苷注射剂制剂置于4℃条件下密封保存，可直接作为静脉注射剂使用，或者加入到5％葡萄糖溶液或者生理盐水中供静脉滴注使用。
实施例6
取500mg磺丁基-β-环糊精、2400mg的PEG400、100mg的PVP k30、25mg的甘氨酸溶解于3mL的注射用水中制备为水相。
取25mg替尼泊苷加5mL丙酮，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌1小时后，低负压下(-0.01～-0.03Mpa) 搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，注射用水定容至5mL，即得替尼泊苷注射剂制剂。所得替尼泊苷注射剂制剂置于4℃条件下密封保存，可直接作为静脉注射剂使用，或者加入到5％葡萄糖溶液或者生理盐水中供静脉滴注使用。
实施例7
取500mg磺丁基-β-环糊精、1800mg的PEG400、200mg的PVP k30、50mg的甘氨酸溶解于3mL的注射用水中制备为水相。
取25mg替尼泊苷加5mL丙酮，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌1小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，注射用水定容至5mL，即得替尼泊苷注射剂制剂。所得替尼泊苷注射剂制剂置于4℃条件下密封保存，可直接作为静脉注射剂使用，或者加入到5％葡萄糖溶液或者生理盐水中供静脉滴注使用。
实施例8
取250mg磺丁基-β-环糊精、2500mg的PEG400、250mg的甘氨酸溶解于3mL的注射用水中制备为水相。
取50mg替尼泊苷加5mL丙酮，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌1小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，注射用水定容至5mL，即得替尼泊苷注射剂制剂。所得替尼泊苷注射剂制剂置于4℃条件下密封保存，可直接作为静脉注射剂使用，或者加入到5％葡萄糖溶液或者生理盐水中供静脉滴注使用。
实施例9
取1000mg羟丙基-β-环糊精、1700mg的PEG400、60mg的泊洛沙姆、60mg的甘氨酸溶解于3mL的注射用水中制备为水相。
取50mg替尼泊苷加5mL乙醇，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌0.5小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，注射用水定容至5mL，即得替尼泊苷注射剂制剂。所得替尼泊苷注射剂制剂置于4℃条件下密封保存，可直接作为静脉注射剂 使用，或者加入到5％葡萄糖溶液或者生理盐水中供静脉滴注使用。
实施例10
取1000mg羟丙基-磺丁基-β-环糊精、1700mg的PEG400、60mg的泊洛沙姆、60mg的甘氨酸溶解于3mL的注射用水中制备为水相。
取50mg替尼泊苷加5mL乙醇，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌0.5小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，注射用水定容至5mL，即得替尼泊苷注射剂制剂。所得替尼泊苷注射剂制剂置于4℃条件下密封保存，可直接作为静脉注射剂使用，或者加入到5％葡萄糖溶液或者生理盐水中供静脉滴注使用。
对比例1
按照市售替尼泊苷注射液处方制备对比例1，取50mg替尼泊苷，300mgN，N二甲基乙酰胺，150mg苯甲醇，2500mg聚氧乙基化蓖麻油,调pH至5左右的适量马来酸和42.7％(v/v,以制剂总体积为基准,下同)的无水乙醇，搅拌均匀后作为稀释稳定性对比的市售对照组。
对比例2
取600mg磺丁基-β-环糊精溶解于5mL的注射用水中制备为水相。
取50mg替尼泊苷加5mL丙酮，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌1小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，静置1天出现析晶。
对比例3
取250mg磺丁基-β-环糊精溶解于5mL的注射用水中制备为水相。
取50mg替尼泊苷加入水相。
在室温下，充分搅拌3小时后，不能制成澄清溶液。
对比例4
取600mg磺丁基-β-环糊精溶解于5mL的注射用水中制备为水相。
取50mg替尼泊苷加入水相。
在室温下，充分搅拌3小时后，不能制成澄清溶液。
对比例5
取600mg磺丁基-β-环糊精、60mg的甘氨酸溶解于5mL的注射用水中制备为水相。
取50mg替尼泊苷加5mL丙酮，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌1小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，静置1天出现析晶。
对比例6
取600mg磺丁基-β-环糊精、60mg的PVPK17溶解于5mL的注射用水中制备为水相。
取50mg替尼泊苷加5mL丙酮，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌1小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，静置1天出现析晶。
对比例7
取600mg磺丁基-β-环糊精、60mg的柠檬酸溶解于5mL的注射用水中制备为水相。
取50mg替尼泊苷加5mL丙酮，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌1小时后，低负压下(-0.01～-0.03Mpa)搅拌2小时后，高真空状态(约为-0.1Mpa)搅拌1小时，静置1天出现析晶。
对比例8
取600mg磺丁基-β-环糊精、2000mg的PEG300、60mg的PVP k12、60mg的柠檬酸溶解于3mL的注射用水中制备为水相。
取50mg替尼泊苷加2.5mL乙醇和2.5mL丙酮溶解，制备为有机相。
在室温下，边搅拌边将有机相加入水相，充分搅拌3小时后，高真空状态(约为-0.1Mpa)搅拌1小时，注射用水定容至5mL，即得替尼泊苷组合物。所得替尼泊苷混合物置于4℃条件下密封保存，可直接作为静脉注射剂使用，或者加入到5％葡萄糖溶液或者生理盐水中供静脉滴注使用。
效果实验例1：
对比例2、5、6、7、8存在存放中主药析出的现象，对比例3、4不能制备出理想的注射用水溶液，本效果实验例对实施例1～8和对比例1、8所制得替尼泊苷组合物进行稀释稳定性实验，该实验记录替尼泊苷组合物用生理盐水或5％葡萄糖溶液稀释至50mL、100mL、250mL和500mL，每个稀释体积制备6份，置于室温和自然光照条件下静置0.5小时和12小时沉淀情况。记录出现沉淀的样品数量。由表1和表2结果可见，随着稀释体积和静置时间的增加，仿市售制剂出现沉淀的比例显著增加，实施例1-8所制备的样品要稀释实验中稳定性表现优异。分低真空和高真空两步抽离有机溶剂比直接在高真空抽离有机溶剂的稳定性要好。在稀释操作过程中，我们还发现仿市售制剂吸取和注射过程中应尽量动作轻缓，否则会快速析晶，而本发明提供的注射剂不存在此现象。表1和表2的结果还标明，仿市售制剂和本发明中的制剂在生理盐水和5％葡萄糖稀释液中的稀释稳定性没有差异。
表1：生理盐水稀释替尼泊苷组合物沉淀情况
Figure PCTCN2018110655-appb-000001
表2：5％葡萄糖稀释替尼泊苷组合物沉淀情况
Figure PCTCN2018110655-appb-000002
Figure PCTCN2018110655-appb-000003
本发明中的替尼泊苷组合物避免了使用副作用较大的苯甲醇、二甲基乙酰胺和聚氧乙烯蓖麻油等辅料，可预见的降低辅料引起的副作用，提高患者使用顺应度。
在稀释过程中，仿市售制剂需操作轻柔，过于剧烈的将注射液注入稀释溶剂中会加大结晶析出的可能性，本发明制剂不存在此项缺陷，降低了药液配制对最终输液质量造成影响的风险，方便医护人员的使用。
本发明中的替尼泊苷组合物成功解决了市售替尼泊苷注射液在稀释过程中极易析出、形成沉淀的弊端，降低了输注针头或血管堵塞的风险，方便临床使用。
本发明通过对减压抽离有机溶剂的过程进行优化，改善了产品在稀释过程中不稳定的缺陷。

Claims (10)

  1. 一种替尼泊苷组合物，其特征在于由替尼泊苷和环糊精组成，替尼泊苷：环糊精质量比为1：5～20，优选1:10-15；进一步优选1:12。
  2. 根据权利要求1所述的组合物，其特征在于所述的环糊精选自羟丙基-β-环糊精、磺丁基醚-β-环糊精、羟丙基-磺丁基醚-β-环糊精、甘露糖基-β-环糊精或半乳糖基-β-环糊精中的一种或多种；优选磺丁基-β-环糊精。
  3. 权利要求1或2所述的替尼泊苷组合物在制备替尼泊苷注射用溶液或粉针中的应用。
  4. 一种替尼泊苷注射用溶液或粉针，其特征在于除包含权利要求1或2的组合物外，还包含稳定剂和附加剂。
  5. 根据权利要求4所述的替尼泊苷注射用溶液或粉针，其特征在于所述的稳定剂选自聚乙烯吡咯烷酮、聚乙烯醇、十二烷基磺酸钠、十二烷基硫酸钠、泊洛沙姆、聚乙二醇中的任意一种或多种；替尼泊苷与稳定剂的质量比为1：20～100，优选1：35～80，进一步优选1:40～50。
  6. 根据权利要求4所述的替尼泊苷注射用溶液或粉针，其特征在于所述附加剂选自渗透压调节剂、pH值调节剂、金属离子络合剂、抗氧剂中的任意一种或多种；所述渗透压调节剂选自丙二醇、丙三醇、甘露醇中的任意一种或多种；所述pH值调节剂选自盐酸、硫酸、磷酸、柠檬酸、山梨酸、硫辛酸、氢氧化钠、碳酸氢钠、甘氨酸、磷酸二氢钠中的任意一种或多种；所述金属离子络合剂选自乙二胺四乙酸、乙二胺四乙酸钠盐、乙二胺四乙酸钾盐中的任意一种或多种；所述抗氧剂选自亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代硫酸钠、维生素C中的任意一种或多种；替尼泊苷与附加剂的质量比为1：1～10，进一步优选1:1～5。
  7. 根据权利要求4所述的替尼泊苷注射用溶液或粉针，其特征在于所述的替尼泊苷注射用溶液或粉针主要包含以下组分：替尼泊苷、环糊精、稳定剂、附加剂及注射用水；其中替尼泊苷：环糊精质量比为1：5～20；替尼泊苷与稳定剂的质量比为1：20～100；替尼泊苷与附加剂的质量比为1：1～10。
  8. 根据权利要求4所述的替尼泊苷注射用溶液或粉针，其特征在于所述的替尼泊苷注射用溶液主要通过下列步骤制备得到：
    1)取环糊精、稳定剂和附加剂溶于注射用水为水相,其中环糊精在水相中的终浓度为5％～35％，优选15％～35％；
    2)取替尼泊苷，溶于有机溶剂中为有机相,替尼泊苷在有机相中的终浓度为0.5％～1％；所述有机溶剂选自丙酮、甲醇、乙醇或氯仿中的任意一种或多种；
    3)将步骤2)所得有机相与步骤1)所得水相充分混合后，除去有机溶剂，注射用水定容，即得替尼泊苷组合物。
  9. 权利要求4所述的替尼泊苷注射用溶液的制备方法，其特征在于包括下列步骤：
    1)取环糊精、稳定剂和附加剂溶于注射用水为水相，其中环糊精在水相中的终浓度为5％～35％，优选15％～35％；
    2)取替尼泊苷，溶于有机溶剂中为有机相,替尼泊苷在有机相中的终浓度为0.5％～1％；所述有机溶剂选自丙酮、甲醇、乙醇或氯仿中的任意一种或多种；
    3)按照替尼泊苷：环糊精质量比为1：5～20，将步骤2)所得有机相与步骤1)所得水相充分混合后，除去有机溶剂，注射用水定容，即得替尼泊苷组合物。
  10. 根据权利要求9所述的制备方法，其特征在于除去有机溶剂的步骤为：在室温下，边搅拌边将有机相加入水相，充分搅拌0.5小时后，低负压下继续搅拌2小时后，高真空状态继续搅拌1小时；所述的低负压条件为-0.01～-0.03Mpa，所述的高真空状态的压力为-0.1Mpa。
PCT/CN2018/110655 2018-10-17 2018-10-17 一种稀释稳定性好的替尼泊苷注射用溶液及其制备方法 WO2020077564A1 (zh)

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