WO2019136817A1 - 一种注射用卡巴他赛组合物及其制备方法 - Google Patents

一种注射用卡巴他赛组合物及其制备方法 Download PDF

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WO2019136817A1
WO2019136817A1 PCT/CN2018/078567 CN2018078567W WO2019136817A1 WO 2019136817 A1 WO2019136817 A1 WO 2019136817A1 CN 2018078567 W CN2018078567 W CN 2018078567W WO 2019136817 A1 WO2019136817 A1 WO 2019136817A1
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composition
cabazitaxel
parts
stir
peg
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PCT/CN2018/078567
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English (en)
French (fr)
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童克勤
成金兰
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比卡生物科技（广州）有限公司
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Priority to US16/652,356 priority Critical patent/US20200268705A1/en
Priority to EP18900288.4A priority patent/EP3698812A4/en
Priority to JP2020528900A priority patent/JP7016415B2/ja
Publication of WO2019136817A1 publication Critical patent/WO2019136817A1/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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K47/30—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
    • A61K47/36—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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides

Definitions

  • the invention relates to the technical field of pharmaceutical preparations, in particular to a cabazitaxel composition for injection and a preparation method thereof.
  • Cabazitaxel is a white or off-white powder that is almost insoluble in water, soluble in ethanol, and unstable under alkaline conditions.
  • the chemical name is (1S, 2S, 3R, 4S, 7R, 9S, 10S, 12R, 15S)-4-acetoxy-15- ⁇ [(2R,3S)-3- ⁇ [(tert-butoxy)carbonyl Amino] ⁇ -2-hydroxy-3-phenylpropionyl]oxy ⁇ -1-hydroxy-9,12-dimethoxy-10,14,17,17-tetramethyl-11-oxo-6 -oxatetracyclo[11.3.1.0 3; 10.4 4;7 ]heptadeca-13-en-2-ylbenzoate.
  • Molecular formula C 45 H 57 N 14 molecular weight 835.93, the structural formula is as follows:
  • Cabazitaxel is a new generation of taxane antitumor drugs, which can be obtained by semi-synthesis of precursors extracted from yew. Its anti-cancer mechanism and characteristics are similar to docetaxel, and it belongs to anti-microtubule drugs. Cabazitaxel promotes its assembly into microtubules by binding to tubulin, while preventing the disassembly of these assembled microtubules, stabilizing the microtubules, and thereby inhibiting cell mitosis and interphase cell function. Compared with paclitaxel and docetaxel, cabazitaxel has a stronger ability to inhibit tumor cell proliferation and is effective against docetaxel-resistant tumor patients. In 2010, the US FDA approved the drug formulation developed by Sanofi-Aventis. It is the first FDA-approved treatment for prostate cancer that is resistant to docetaxel and can significantly prolong the survival of patients with advanced prostate cancer.
  • Cabazitaxel is highly lipophilic and almost insoluble in water, its commercial preparations
  • the surfactant polysorbate 80 (Tween 80) was used as a solubilizer and ethanol was used as a diluent.
  • the package specification contains two vials: (a) Injectable, 60 mg of cabazitaxel was dissolved in 1.5 mL of polysorbate 80; (b) diluent, 13% (w/w) of ethanol solution about 5.7 mL.
  • This preparation requires a two-step preparation process before administration to the patient: the first step will be (a) The injection is mixed with (b) a diluent at a concentration of about 10 mg/mL; in the second step, the above mixture is diluted into a 250 mL container (non-PVC) containing a 0.9% sodium chloride solution for injection or a 5% glucose solution.
  • concentration of cabazitaxel in the final infusion solution should be from 0.1 mg/mL to 0.26 mg/mL.
  • Polysorbate is a nonionic surfactant with an unusual odor, warm and slightly bitter, and is a series of fatty acid esters of polyoxyethylene sorbitan. Widely used as a solubilizer for emulsifiers and oils. Polysorbate is generally considered to be a non-toxic, non-irritating material and is often used as a solubilizing adjuvant for injectable, poorly soluble drugs. However, due to the side effects of Tween injection, low concentrations (0.01 to 2.0%) can be produced.
  • Polysorbate 80 at The presence may cause serious side effects, and such reactions characterized by systemic rash/erythema, hypotension, and/or bronchospasm or very rare fatal allergic reactions have been reported in patients.
  • antihistamine antihistamine
  • corticosteroids corticosteroid
  • H 2 antagonists H 2 antagonist
  • the medicinal excipient cyclodextrin has a hollow hydrophobic stereogenic chiral cavity, and its "internal hydrophobic, external hydrophilic" structural properties encapsulate a variety of small organic molecules (substrate) suitable for spatial size, forming non-covalent
  • the most prominent pharmaceutical effect of the host-guest complex (clustered compound) is to increase the water solubility of the poorly soluble drug and increase the stability of the drug.
  • a composition of Cabazitaxel and sulfobutylether beta-cyclodextrin (SBE- ⁇ -CD) in a weight ratio of 1:30 to 1:1000 is disclosed in the patent application CA2900508A1 (US20150325321A1) by Valery Alakhov et al.
  • Such as The specification is 60mg/1.5mL, calculated according to the solubility of Cabazitaxel in a 40% concentration of SBE- ⁇ -CD aqueous solution of about 1mg/mL, 60ml of this solution is needed to dissolve 60mg of Cabazitaxel; if it is calculated according to the solubility of 4.17mg/mL, 60mg is dissolved.
  • Cabazitaxel also requires about 15 mL of this solution, compared to The volume of 1.5mL per vial is too different, so it is difficult to industrially produce from the aspects of preparation process, cost, packaging, transportation, storage and so on. At the same time, it is necessary to consider whether Cabazitaxel injection is stable or does not precipitate crystals or precipitates when diluted with the infusion solution 0.9% sodium chloride solution or 5% glucose solution to the infusion concentration range.
  • the inventors of the present application have broken through the prejudice of the prior art, reversed the existing cognition, reduced the amount of cyclodextrin, and abandoned the use of a highly stimulating ethanol solvent and side reactions.
  • Tween 80 added an injectable additive to a solution system consisting of 700 mg/ml PEG300, 290 mg/ml SBE- ⁇ -CD, 80 mg/ml PVPK12, and an appropriate amount of water (about 100 mg): such as citric acid, hydrogen sulfite.
  • the prepared composition can make the solubility of cabazitaxel ⁇ 40 mg / mL, and at the same time greatly improve the stability of cabazitaxel in the system. Sex.
  • cabazitaxel cyclodextrin, polyethylene glycol (PEG), povidone (PVP) and A new composition consisting of an injectable additive, and the composition is free of polysorbate and ethanol, can significantly improve the characteristics of the cabazitaxel formulation, and can effectively increase the solubility and stability of cabazitaxel.
  • PEG polyethylene glycol
  • PVP povidone
  • the object of the present invention is to develop a single-bottle ready-to-use type without polysorbate and ethanol in view of the deficiencies in the prior art, without requiring two-step dilution, stable properties, meeting clinical drug needs, and ensuring the safety of medication. Sexually effective injections of cabazitaxel.
  • a single vial ready-to-use type refers to a sterile liquid or lyophilizate in a single vial that can be administered intravenously to a patient after dilution or dissolution with an infusion solution to a clinically applied concentration range, without requiring two steps dilution.
  • infusion solution is meant a sterile isotonic solution, such as a 0.9% sodium chloride solution or a 5% dextrose solution, which is typically stored in a bag or vial for administration to a patient after dilution or dissolution of the diluted injectable preparation.
  • a sterile isotonic solution such as a 0.9% sodium chloride solution or a 5% dextrose solution, which is typically stored in a bag or vial for administration to a patient after dilution or dissolution of the diluted injectable preparation.
  • the present invention adopts the following technical solutions:
  • the present invention provides a cabazitaxel composition for injection comprising the following components by weight: cabazitaxel: 1 part, cyclodextrin: 1 to 100 parts, cosolvent: 10 to 200 Parts, povidone (PVP): 1 to 60 parts, an additive 0.02 to 1.0 part, and the composition does not contain polysorbate (for example, Tween 80) and ethanol.
  • cabazitaxel 1 part
  • cyclodextrin 1 to 100 parts
  • cosolvent 10 to 200 Parts
  • povidone (PVP) 1 to 60 parts
  • an additive 0.02 to 1.0 part an additive 0.02 to 1.0 part
  • the composition does not contain polysorbate (for example, Tween 80) and ethanol.
  • the composition comprises the following components by weight: cabazitaxel: 1 part, cyclodextrin: 10 to 30 parts, cosolvent: 30 to 150 parts, povidone (PVP): 1 to 15 parts
  • the additive is 0.05-0.8 parts, and the composition does not contain polysorbate and ethanol.
  • the composition comprises the following components by weight: cabazitaxel: 1 part, cyclodextrin: 25 to 29 parts, cosolvent: 50 to 90 parts, povidone (PVP): 7 to 15 Parts and additives are 0.05 to 0.8 parts, and the composition does not contain polysorbate and ethanol.
  • the composition comprises the following components by weight: cabazitaxel: 1 part, cyclodextrin: 26 to 29 parts, cosolvent: 60 to 80 parts, povidone (PVP): 7 to 10 parts, an additional dose of 0.1 to 0.7 parts, and the composition does not contain polysorbate and ethanol.
  • the cyclodextrin comprises, but is not limited to, sulfobutyl ether beta-cyclodextrin (SBE- ⁇ -CD), hydroxypropyl beta-cyclodextrin (HP- ⁇ -CD) and/or hydroxypropyl Sulfobutyl ether beta-cyclodextrin (HP-SBE- ⁇ -CD); preferably SBE- ⁇ -CD.
  • SBE- ⁇ -CD sulfobutyl ether beta-cyclodextrin
  • HP- ⁇ -CD hydroxypropyl beta-cyclodextrin
  • HP-SBE- ⁇ -CD hydroxypropyl Sulfobutyl ether beta-cyclodextrin
  • the cosolvent is selected from one or more of polyethylene glycol (PEG), propylene glycol and glycerin, preferably polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • PEG polyethylene glycol
  • the polyethylene glycol (PEG) is selected from, but not limited to, one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 1500, and PEG 2000, preferably PEG 300 and/or PEG 400.
  • the povidone (PVP) is selected from, but not limited to, one of PVPK12, PVPK15, PVPK17, PVPK25, PVPK30, PVPK45, PVPK60, PVPK70, PVPK80, PVPK85, PVPK90, PVPK100, PVPK110, PVPK120 and PVPK150 or A variety of, preferably PVPK12 and / or PVPK17.
  • the additional agent includes, but is not limited to, citric acid and/or tartaric acid; and/or acetic acid; and/or hydrochloric acid; and/or phosphoric acid; and/or lactic acid; and/or ascorbic acid; and/or L-cysteine.
  • citric acid and/or tartaric acid and/or acetic acid; and/or hydrochloric acid; and/or phosphoric acid; and/or lactic acid; and/or ascorbic acid; and/or L-cysteine.
  • sodium hydrogen sulfite; and/or sodium metabisulfite; and/or disodium edetate preferably citric acid and/or sodium hydrogen sulfite.
  • the composition is in the form of a solid lyophilizate or an aqueous solution suitable for storage.
  • the present invention provides a method for preparing the aforementioned cabazitaxel composition for injection (a soft lyophilizate for injection of a cabazitaxel composition), the method comprising the steps of:
  • the uniform mixed solution has a pH of 2.0 to 6.0.
  • the present invention provides the aforementioned method for preparing a cabazitaxel composition for injection (a soft lyophilizate for injection of a cabazitaxel composition), the method comprising the steps of:
  • the uniform mixed solution has a pH of 2.0 to 6.0.
  • the present invention provides a method of treating a tumor comprising administering to a patient in need of administration a composition prepared by the aforementioned composition or preparation method; preferably, the tumor is prostate cancer, the prostate cancer
  • the prostate cancer for prostate cancer, which is difficult to treat with metastatic prostate cancer or tolerant to docetaxel, this treatment can significantly prolong the survival of patients with advanced prostate cancer.
  • the present invention provides excellent stability for the injection of cabazitaxel, and the stabilization time of the related substances and reconstitution is better than the existing commercial preparations.
  • the composition obtained by the present invention does not contain polysorbate (such as Tween 80) and ethanol, and the release of low histamine does not require the use of antihistamines, corticosteroids and H 2 antagonists before administration, single vial ready-to-use type.
  • a new composition preparation without two-step dilution the preparation has the characteristics of high solubility, high stability, long reconstitution stability of the preparation, convenient clinical use, etc., and the allergy is reduced due to the absence of polysorbate and ethanol. Sexual, irritating, addictive and other side effects.
  • the present invention also provides a preparation method of the cabazitaxel composition for injection.
  • Example 1 Comparing the results of Example 1 above with Comparative Example 4 and Example 1 and Example 12, it is understood that when the amount of cyclodextrin is within the preferred range of the present invention (Example 1 SBE- ⁇ -CD 29g), the preparation is clarified and reconstituted into Clear solution, stabilization time about 8h, then crystallization; preparation does not contain cyclodextrin (Comparative Example 4 acyclodextrin) or cyclodextrin dosage is lower than the preferred range of the invention (Example 12 SBE- ⁇ -CD 10g The resulting preparation was crystallized and precipitated about 1 hour upon reconstitution.
  • Example 2 SBE- ⁇ -CD 29g the amount of cyclodextrin is within the preferred range
  • Example 3 SBE- ⁇ -CD 40g the amount of cyclodextrin is outside the preferred range
  • the preparations were all clarified, reconstituted into a clear solution, the stabilization time was about 8h, and then crystallization, there was no significant difference between the two prescription preparations.
  • cyclodextrin A preferred choice is when the amount is within the preferred range.
  • the amount of cyclodextrin is less than that of the formulation, and the preparation time is not stable, and the amount of the preparation is not significantly improved.

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Abstract

本发明涉及一种注射用卡巴他赛组合物及其制备方法。所述组合物包括如下重量份的组分：卡巴他赛：1 份、环糊精：1～100 份、助溶剂：10～200 份、聚维酮 (PVP)：1～60 份、附加剂 0.02～1.0 份，且该组合物不含聚山梨酯和乙醇。本发明的组合物不含聚山梨酯和乙醇，低组胺释放，给药前无需使用抗组胺剂、皮质类固醇和 H2 拮抗剂，单小瓶即用型，无需两步稀释的新的组合物制剂，该制剂具有卡巴他赛溶解度高、稳定性高、制剂复溶稳定时间长、临床使用方便等特点，由于不含聚山梨酯和乙醇，降低了过敏性、刺激性、成瘾性等副作用。同时，本发明还获得了一种该注射用卡巴他赛组合物的制备方法。

Description

一种注射用卡巴他赛组合物及其制备方法
相关申请的交叉引用
本申请要求2018年01月11日递交的中国专利申请号为201810025193.4的专利申请的权益，在此将其全部内容引入作为参考。
发明领域
本发明涉及药物制剂技术领域，具体涉及一种注射用卡巴他赛组合物及其制备方法。
技术背景
卡巴他赛(Cabazitaxel)为白色或类白色粉末，几乎不溶于水，可溶于乙醇，且在碱性条件下不稳定。化学名称为(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-乙酰氧基-15-{[(2R,3S)-3-{[(叔丁氧基)羰基氨基]}-2-羟基-3-苯基丙酰基]氧基}-1-羟基-9,12-二甲氧基-10,14,17,17-四甲基-11-氧代-6-氧杂四环[11.3.1.0 3；10.0 4；7]十七碳-13-烯-2-基苯甲酸酯。分子式C 45H 57N 14，分子量835.93，结构式如下：
Figure PCTCN2018078567-appb-000001
卡巴他赛是新一代紫杉烷类抗肿瘤药物，可通过由红豆杉萃取的前体半合成制得，其抗癌作用机制和特点与多西他赛相似，属于抗微管类药物。卡 巴他赛通过与微管蛋白结合，促进其组装成微管，同时可阻止这些已组装好了的微管解体，使微管稳定，进而抑制细胞的有丝分裂和间期细胞功能的发挥。与紫杉醇和多西他赛相比，卡巴他赛抑制肿瘤细胞增殖的能力更强，并对多西他赛耐药的肿瘤患者有效。2010年美国FDA批准由赛诺菲-安万特(Sanofi-aventis)公司开发生产的卡巴他赛药物制剂
Figure PCTCN2018078567-appb-000002
用于激素难治疗转移性前列腺癌的治疗，是FDA批准的第一个用于对多西他赛产生耐受的前列腺癌的治疗药物，能够显著延长晚期前列腺癌患者的生存期。
卡巴他赛亲脂性强，几乎不溶于水，其商用制剂
Figure PCTCN2018078567-appb-000003
采用表面活性剂聚山梨酯80(吐温80)作为增溶剂并且采用乙醇作为稀释剂。制剂包装规格含两个小药瓶：(a)
Figure PCTCN2018078567-appb-000004
注射剂，60mg卡巴他赛溶于1.5mL聚山梨酯80；(b)稀释剂，13％(w/w)的乙醇溶液约5.7mL。这种制剂在向病人给药前还需两步配制过程：第一步将(a)
Figure PCTCN2018078567-appb-000005
注射剂与(b)稀释剂混合，浓度约10mg/mL；第二步将上步混合液稀释入含有注射用0.9％氯化钠溶液或5％葡萄糖溶液的250mL容器(非PVC)。最终配制的输注液中卡巴他赛的浓度应为0.1mg/mL～0.26mg/mL。
聚山梨酯(吐温)为非离子型表面活性剂，有异臭，温暖而微苦，系一系列聚氧乙烯去水山梨醇的部分脂肪酸酯。广泛用作乳化剂和油类物质的增溶剂。聚山梨酯通常被认为是无毒、无刺激性的材料，常用作注射型难溶性药物的增溶辅料，但由于吐温注射给药的副作用，低浓度(0.01～2.0％)时即可产生溶血作用，在局部和肌注时，出现过敏反应，严重时会产生全身性皮疹/红斑、低血压和/或支气管痉挛或非常少见的致命性过敏反应的此类反应甚至死亡的个例，为了降低聚山梨酯的副作用，临床需要给病人抗组胺药(antihistamine)、皮质类固醇(corticosteroid)和H 2拮抗剂(H 2antagonist)预防给药，大大降低了临床使用的顺应性。
聚山梨酯80在
Figure PCTCN2018078567-appb-000006
中的存在可能导致严重副作用，已经报道了在患者中特征为全身性皮疹/红斑、低血压和/或支气管痉挛或非常少见的致命性过敏反应的此类反应。为了降低由聚山梨酯80诱导的副作用，
Figure PCTCN2018078567-appb-000007
Figure PCTCN2018078567-appb-000008
静脉给药前30分钟应给病人以抗组胺药(antihistamine)、皮质类固醇 (corticosteroid)和H 2拮抗剂(H 2antagonist)事先用药。同时
Figure PCTCN2018078567-appb-000009
临床使用前需要进行两步稀释：即先用13％(w/w)的乙醇液稀释，再用0.9％氯化钠溶液或5％葡萄糖溶液稀释后方可给药，使用步骤繁琐，存在用药方面的安全隐患。另外，
Figure PCTCN2018078567-appb-000010
采用13％(w/w)的乙醇溶液做稀释剂，然而乙醇在注射给药时会产生较大的刺激以及成瘾性等副作用。
因此，需要卡巴他赛的新制剂在临床应用中尽可能少副作用、无前驱给药需求以及使用步骤更简单、安全、易操作。
药用辅料环糊精有一个中空的疏水立体手性内腔，其“内疏水，外亲水”的结构特性能包封多种空间尺寸适合的有机小分子(底物)，形成非共价主-客体复合物(包合物)，其最显著的药学作用便是增加难溶药的水溶性和增加药物的稳定性。如Valery Alakhov等人的发明申请CA2900508A1(US20150325321A1)公开了卡巴他赛(Cabazitaxel)与磺丁基醚倍他环糊精(SBE-β-CD)重量比在1:30～1:1000的组合物，其实验结果显示在40％浓度的SBE-β-CD水溶液中Cabazitaxel的溶解度为4.17mg/mL。但是本发明申请人在实验研究SBE-β-CD对Cabazitaxel增溶作用时发现40％浓度的SBE-β-CD水溶液中Cabazitaxel的溶解度约1mg/mL，无法达到CA2900508A1专利所述的4.17mg/mL的浓度，即使能达到该浓度，也很难实现制备合乎市售制剂浓度规格的Cabazitaxel注射剂。如
Figure PCTCN2018078567-appb-000011
规格为60mg/1.5mL，按40％浓度的SBE-β-CD水溶液中Cabazitaxel的溶解度约1mg/mL计算，溶解60mg的Cabazitaxel需要60mL该溶液；若按溶解度为4.17mg/mL计算，溶解60mg的Cabazitaxel也需要约15mL该溶液，相比
Figure PCTCN2018078567-appb-000012
每小瓶1.5mL的体积实在相差太多，这样从制备工艺、成本、包装、运输、储存等方面考虑都是难以工业化生产的。同时需要考虑的是Cabazitaxel注射剂在用输注溶液0.9％氯化钠溶液或5％葡萄糖溶液稀释到输注浓度范围内时是否稳定、不析出晶体或沉淀物。
基于市售制剂
Figure PCTCN2018078567-appb-000013
的配方含有聚山梨酯和乙醇以及CA2900508A1(US20150325321A1)专利的配方含有高比例(大于1：30)环糊精的启发，一种显而易见的结果是，继续提高环糊精的比例和/或者增加 配方中的乙醇量才能满足替代聚山梨酯的制剂配方，但本发明人的这种尝试得到的结果是，无论是提高环糊精含量还是增加乙醇用量都不能提高卡巴他赛溶解度，以满足临床用药的需求。
发明内容
考虑到现有技术的种种缺陷，本申请的发明人突破了现有技术的偏见，对已有认知的逆向试验，降低环糊精的用量同时放弃使用刺激强的乙醇溶剂和有副反应的吐温80。具体而言，本申请的发明人向700mg/mlPEG300、290mg/mlSBE-β-CD、80mg/mlPVPK12及适量水(约100mg)组成的溶液体系中加入注射用附加剂：如柠檬酸、亚硫酸氢钠、依地酸二钠等，并充入适量的氮气，结果发现，制备得到的组合物既能使卡巴他赛的溶解度≥40mg/mL，同时又能大大提高卡巴他赛在该体系中稳定性。
换句话说，根据本申请的发明人的逆向试验，得到一种非显而易见、甚至出乎意料的结果：卡巴他赛、环糊精、聚乙二醇(PEG)、聚维酮(PVP)及注射用附加剂组成的新的组合物，并且该组合物不含聚山梨酯和乙醇，可以显著改进卡巴他赛制剂特性，并能有效地增加卡巴他赛的溶解度和稳定性。
研究表明，卡巴他赛、环糊精、PEG、PVP组成的不含聚山梨酯和乙醇的组合物体系，既可以克服现有市售制剂含聚山梨酯而导致的副作用，又能大大降低制剂的注射刺激性以及用药的成瘾性，并且使得卡巴他赛制剂稳定性大大提高。该技术方案克服了专利CA2900508A1大量使用环糊精但并不能显著提高卡巴他赛的溶解度，最高只能增加到4.17mg/mL的缺陷，并且克服了CA2900508A1中形成的卡巴他赛组合物稳定性不高，难以满足临床使用的实用性问题。
为此，本发明的目的在于：针对现有技术中存在的不足，开发不含聚山梨酯以及乙醇，单小瓶即用型，无需两步稀释，性质稳定、满足临床用药需求并保证用药的安全性有效性的注射用卡巴他赛。
定义
单小瓶即用型是指在单个小药瓶中的无菌液体或冻干物，其在用输注溶 液稀释或溶解稀释到临床应用浓度范围内后可以通过静脉向患者给药，无需两步稀释。
输注溶液是指通常贮存在袋或瓶中的用于稀释或溶解稀释注射用制剂后可以向患者给药的无菌等渗溶液，如0.9％氯化钠溶液或5％葡萄糖溶液。
技术方案
为实现上述目的，本发明采用如下技术方案：
一方面，本发明提供一种注射用卡巴他赛组合物，所述组合物包括如下重量份的组分：卡巴他赛：1份、环糊精：1～100份、助溶剂：10～200份、聚维酮(PVP)：1～60份、附加剂0.02～1.0份，且该组合物不含聚山梨酯(例如吐温80)和乙醇。
优选地，所述组合物包括如下重量份的组分：卡巴他赛：1份、环糊精：10～30份、助溶剂：30～150份、聚维酮(PVP)：1～15份、附加剂0.05～0.8份，且该组合物不含聚山梨酯和乙醇。
更优选地，所述组合物包括如下重量份的组分：卡巴他赛：1份、环糊精：25～29份、助溶剂：50～90份、聚维酮(PVP)：7～15份、附加剂0.05～0.8份，且该组合物不含聚山梨酯和乙醇。
进一步优选地，所述组合物包括如下重量份数的组分：卡巴他赛：1份、环糊精：26～29份、助溶剂：60～80份、聚维酮(PVP)：7～10份、附加剂0.1～0.7份，且该组合物不含聚山梨酯和乙醇。
优选地，所述环糊精包括但不限于磺丁基醚倍他环糊精(SBE-β-CD)、羟丙基倍他环糊精(HP-β-CD)和/或羟丙基磺丁基醚倍他环糊精(HP-SBE-β-CD)；优选为SBE-β-CD。
优选地，所述助溶剂选自但不限于聚乙二醇(PEG)、丙二醇和甘油中的一种或多种，优选为聚乙二醇(PEG)。
优选地，所述聚乙二醇(PEG)选自但不限于PEG200、PEG300、PEG400、PEG600、PEG800、PEG1000、PEG1500和PEG2000中的一种或多种，优选为PEG300和/或PEG400。
优选地，所述聚维酮(PVP)选自但不限于PVPK12、PVPK15、PVPK17、PVPK25、PVPK30、PVPK45、PVPK60、PVPK70、PVPK80、PVPK85、PVPK90、PVPK100、PVPK110、PVPK120和PVPK150中的一种或多种，优选为PVPK12和/或PVPK17。
优选地，所述附加剂包括但不限于柠檬酸和/或酒石酸；和/或醋酸；和/或盐酸；和/或磷酸；和/或乳酸；和/或抗坏血酸；和/或L-半胱氨酸；和/或 亚硫酸氢钠；和/或焦亚硫酸钠；和/或依地酸二钠，优选为柠檬酸和/或亚硫酸氢钠。
优选地，所述组合物为固体冻干物形式或适于储存的水溶液形式。
另一方面，本发明提供前述的注射用卡巴他赛组合物(注射用卡巴他赛组合物固体冻干物)的制备方法，该制备方法包括以下步骤：
(1)称取环糊精，加入助溶剂和水，搅拌溶解后加入聚维酮及附加剂，搅拌溶解，再加入卡巴他赛并充惰性气体(例如氮气)保护，搅拌溶解后继续搅拌30～240min，获得均一的混合溶液；
(2)取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，半压塞，置冷冻干燥机中冷冻干燥，充氮，压塞，轧盖，贴标即得。
优选地，在步骤(1)中，所述均一的混合溶液的pH值为2.0-6.0。
再一方面，本发明提供前述的注射用卡巴他赛组合物(注射用卡巴他赛组合物固体冻干物)的另一种制备方法，该制备方法包括以下步骤：
(1)称取环糊精，加入助溶剂和水，搅拌溶解后加入聚维酮及附加剂，搅拌溶解，再加入卡巴他赛并充惰性气体(例如氮气)保护，搅拌溶解后继续搅拌30～240min，获得均一的混合溶液；
(2)取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
优选地，在步骤(1)中，所述均一的混合溶液的pH值为2.0～6.0。
又一方面，本发明提供一种治疗肿瘤的方法，该方法包括向需要施用的患者给予前述的组合物或制备方法制备得到的组合物；优选地，所述肿瘤为前列腺癌，所述前列腺癌为用于激素难治疗转移性前列腺癌或对多西他赛产生耐受的前列腺癌，通过该治疗方法能够显著延长晚期前列腺癌患者的生存期。采用上述技术方案，由于助溶剂的溶解、环糊精的包合增溶以及聚维酮的结晶生长阻止剂的协同作用、附加剂调节形成的合适的pH低浓度金属离子以及氮气形成的低氧或近乎低氧体系环境，使得本发明得到注射用卡巴他赛的稳定性极佳、有关物质和复溶的稳定时间均好于现有的市售制剂。
因此，本发明得到的组合物不含聚山梨酯(例如吐温80)和乙醇，低组胺释放，给药前无需使用抗组胺剂、皮质类固醇和H 2拮抗剂，单小瓶即用型，无需两步稀释的新的组合物制剂，该制剂具有卡巴他赛溶解度高、稳定性高、制剂复溶稳定时间长、临床使用方便等特点，由于不含聚山梨酯和乙 醇，降低了过敏性、刺激性、成瘾性等副作用。同时，本发明还获得了一种该注射用卡巴他赛组合物的制备方法。
具体实施方式
下面结合具体实施例对本发明做进一步的说明，但不用来限制本发明的范围。
实施例1
Figure PCTCN2018078567-appb-000014
称取处方量的SBE-β-CD，加入处方量的PEG300和水，23～25℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的亚硫酸氢钠和卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例2
Figure PCTCN2018078567-appb-000015
称取处方量的SBE-β-CD，加入处方量的PEG300和水，22～25℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后， 0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例3
Figure PCTCN2018078567-appb-000016
称取处方量的SBE-β-CD，加入处方量的PEG300和水，18～20℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的卡巴他赛，搅拌溶解后继续搅拌100min使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例4
Figure PCTCN2018078567-appb-000017
称取处方量的SBE-β-CD，加入处方量的PEG300和水，20～22℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的卡巴他赛，搅拌溶解后继续搅拌240min使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，半压塞，置冷冻干燥机中冷冻干燥，压塞，轧盖，贴标即得。
实施例5
Figure PCTCN2018078567-appb-000018
Figure PCTCN2018078567-appb-000019
称取处方量的SBE-β-CD，加入处方量的PEG400和水，21～23℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的亚硫酸氢钠和卡巴他赛，搅拌溶解后继续搅拌30min使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例6
Figure PCTCN2018078567-appb-000020
称取处方量的SBE-β-CD，加入处方量的PEG400和水，19～22℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例7
Figure PCTCN2018078567-appb-000021
Figure PCTCN2018078567-appb-000022
称取处方量的HP-β-CD，加入处方量的PEG300和水，18～20℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的卡巴他赛，搅拌溶解后继续搅拌180min使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例8
Figure PCTCN2018078567-appb-000023
称取处方量的HP-β-CD，加入处方量的PEG300和水，18～20℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的亚硫酸氢钠和卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例9
Figure PCTCN2018078567-appb-000024
称取处方量的HP-SBE-β-CD，加入处方量的PEG300和水，23～25℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的卡巴 他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例10
Figure PCTCN2018078567-appb-000025
称取处方量的HP-SBE-β-CD，加入处方量的PEG300和水，23～25℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，半压塞，置冷冻干燥机中冷冻干燥，压塞，轧盖，贴标即得。
实施例11
Figure PCTCN2018078567-appb-000026
称取处方量的SBE-β-CD，加入处方量的PEG300和水，23～25℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的亚硫酸氢钠和卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例12
Figure PCTCN2018078567-appb-000027
称取处方量的SBE-β-CD，加入处方量的PEG300和水，23～25℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的亚硫酸氢钠和卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例13
Figure PCTCN2018078567-appb-000028
称取处方量的SBE-β-CD，加入处方量的丙二醇和水，23～25℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的亚硫酸氢钠和卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例14
Figure PCTCN2018078567-appb-000029
Figure PCTCN2018078567-appb-000030
称取处方量的SBE-β-CD，加入处方量的甘油和水，23～25℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的亚硫酸氢钠和卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例15
Figure PCTCN2018078567-appb-000031
称取处方量的SBE-β-CD，加入处方量的PEG300和水，23～25℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的亚硫酸氢钠和卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实施例16
Figure PCTCN2018078567-appb-000032
Figure PCTCN2018078567-appb-000033
称取处方量的SBE-β-CD，加入处方量的PEG300和水，23～25℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的亚硫酸氢钠和卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
对比例1
Figure PCTCN2018078567-appb-000034
称取处方量的SBE-β-CD，加入处方量的水，23～25℃下搅拌溶解，加入处方量的PVPK12、柠檬酸及亚硫酸氢钠，搅拌溶解后加入处方量的卡巴他赛，搅拌，不能完全溶解。
对比例2
Figure PCTCN2018078567-appb-000035
称取处方量的SBE-β-CD，加入处方量的PEG300和水，23～25℃下搅拌溶解，加入处方量的柠檬酸，搅拌溶解后加入处方量的亚硫酸氢钠和卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标 即得。
对比例3
Figure PCTCN2018078567-appb-000036
称取处方量的SBE-β-CD，加入处方量的水，23～25℃下搅拌溶解，加入处方量的柠檬酸及亚硫酸氢钠，搅拌溶解后加入处方量的卡巴他赛，搅拌，不能完全溶解。
对比例4
Figure PCTCN2018078567-appb-000037
加入处方量的PEG300和水，23～25℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌溶解后加入处方量的亚硫酸氢钠和卡巴他赛，搅拌溶解后继续搅拌2h使溶液均匀。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
对比例5
Figure PCTCN2018078567-appb-000038
Figure PCTCN2018078567-appb-000039
称取处方量的SBE-β-CD，加入处方量的PEG300和水，23～25℃下搅拌，不能完全溶解，加入处方量的PVPK12及柠檬酸，搅拌，加入处方量的亚硫酸氢钠和卡巴他赛，继续搅拌2h。0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
对比例6
Figure PCTCN2018078567-appb-000040
称取处方量的SBE-β-CD，加入处方量的PEG300和水，23～25℃下搅拌溶解，加入处方量的PVPK12及柠檬酸，搅拌不能全溶，加入处方量的亚硫酸氢钠和卡巴他赛，继续搅拌2h。取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得。
实验例
1、溶解度和复溶对比
按不同的实施例中各物质的比例，制备不含API(卡巴他赛)的空白制剂，然后在分别加入过量的API，于室温避光条件下搅拌12h后，过滤、稀释、测定溶解度；同时按实施例与对比例的制备制剂，考察制剂复溶情况。溶解度及复溶情况对比结果如下：
Figure PCTCN2018078567-appb-000041
Figure PCTCN2018078567-appb-000042
2、对环糊精用量的分析
上表实施例1与对比例4及实施例1与实施例12结果比较可知，环糊精用量在本发明优选范围内(实施例1 SBE-β-CD 29g)时，制剂澄清，复溶为澄明溶液，稳定时间约8h，之后析晶；制剂不含环糊精(对比例4无环糊精)或环糊精用量低于本发明的优选范围时(实施例12 SBE-β-CD 10g)，所得制剂在复溶时约1h析晶沉淀。
上表实施例2与实施例3结果比较可知，环糊精用量在优选范围内(实施例2 SBE-β-CD 29g)和环糊精用量超出优选范围时(实施例3SBE-β-CD  40g)，制剂都澄清，复溶为澄明溶液，稳定时间约8h，之后析晶，两处方制剂无明显差异。从药物制剂的安全考虑，药用辅料或添加剂使用量尽可能少的原则，环糊精用量在优选范围内和高于范围用量时效果等同，或者说增大用量无明显效果，那么环糊精用量在优选范围内则为更好的选择。
综上，环糊精量少制剂复溶稳定不析出的时间较短，量多制剂无明显改善，优选范围内用量更合适。

Claims (11)

  1. 一种注射用卡巴他赛组合物，其特征在于，所述组合物包括如下重量份的组分：卡巴他赛：1份、环糊精：1～100份、助溶剂：10～200份、聚维酮(PVP)：1～60份、附加剂0.02～1.0份，且该组合物不含聚山梨酯和乙醇。
  2. 根据权利要求1所述的组合物，其特征在于，所述组合物包括如下重量份的组分：卡巴他赛：1份、环糊精：10～30份、助溶剂：30～150份、聚维酮(PVP)：1～15份、附加剂0.05～0.8份，且该组合物不含聚山梨酯和乙醇。
  3. 根据权利要求1或2所述的组合物，其特征在于，所述组合物包括如下重量份的组分：卡巴他赛：1份、环糊精：25～29份、助溶剂：50～90份、聚维酮(PVP)：7～15份、附加剂0.05～0.8份，且该组合物不含聚山梨酯和乙醇；
    优选地，所述组合物包括如下重量份的组分：卡巴他赛：1份、环糊精：26～29份、助溶剂：60～80份、聚维酮(PVP)：7～10份、附加剂0.1～0.7份，且该组合物不含聚山梨酯和乙醇。
  4. 根据权利要求1至3中任一项所述的组合物，其特征在于，所述环糊精包括但不限于磺丁基醚倍他环糊精(SBE-β-CD)、羟丙基倍他环糊精(HP-β-CD)和/或羟丙基磺丁基醚倍他环糊精(HP-SBE-β-CD)，优选为SBE-β-CD。
  5. 根据权利要求1至4中任一项所述的组合物，其特征在于，所述助溶剂选自但不限于聚乙二醇(PEG)、丙二醇和甘油中的一种或多种，优选为聚乙二醇(PEG)；
    优选地，所述聚乙二醇(PEG)选自但不限于PEG200、PEG300、PEG400、PEG600、PEG800、PEG1000、PEG1500和PEG2000中的一种或多种，优选为PEG300和/或PEG400。
  6. 根据权利要求1至5中任一项所述的组合物，其特征在于，所述聚维酮(PVP)选自但不限于PVPK12、PVPK15、PVPK17、PVPK25、PVPK30、 PVPK45、PVPK60、PVPK70、PVPK80、PVPK85、PVPK90、PVPK100、PVPK110、PVPK120和PVPK150中的一种或多种，优选为PVPK12和/或PVPK17。
  7. 根据权利要求1至6中任一项所述的组合物，其特征在于，所述附加剂包括但不限于柠檬酸和/或酒石酸；和/或醋酸；和/或盐酸；和/或磷酸；和/或乳酸；和/或抗坏血酸；和/或L-半胱氨酸；和/或亚硫酸氢钠；和/或焦亚硫酸钠；和/或依地酸二钠，优选为柠檬酸和/或亚硫酸氢钠。
  8. 根据权利要求1至7中任一项所述的组合物，其特征在于，所述组合物为固体冻干物形式或适于储存的水溶液形式。
  9. 一种注射用卡巴他赛组合物的制备方法，其特征在于，该制备方法包括如下步骤：
    (1)称取环糊精，加入助溶剂和水，搅拌溶解后加入聚维酮及附加剂，搅拌溶解，再加入卡巴他赛并充惰性气体保护，搅拌溶解后继续搅拌30～240min，获得均一的混合溶液；
    (2)取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，半压塞，置冷冻干燥机中冷冻干燥，充氮、压塞，轧盖，贴标即得；
    优选地，在步骤(1)中，所述均一的混合溶液的pH值为2.0～6.0。
  10. 一种注射用卡巴他赛组合物的制备方法，其特征在于，该制备方法包括如下步骤：
    (1)称取环糊精，加入助溶剂和水，搅拌溶解后加入聚维酮及附加剂，搅拌溶解，再加入卡巴他赛并充惰性气体保护，搅拌溶解后继续搅拌30～240min，获得均一的混合溶液；
    (2)取样测定pH值及含量，合格后，0.2μm聚四氟乙烯(PTFE)膜过滤，西林瓶分装，充氮，压塞，轧盖，贴标即得；
    优选地，在步骤(1)中，所述均一的混合溶液的pH值为2.0～6.0。
  11. 一种治疗肿瘤的方法，该方法包括向需要施用的患者给予权利要求1至8中任一项所述的组合物或权利要求9或10所述的制备方法制备得到的组合物；优选地，所述肿瘤为前列腺癌。
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CN108066774B (zh) 2023-04-18
EP3698812A1 (en) 2020-08-26
JP7016415B2 (ja) 2022-02-04
CN113559277A (zh) 2021-10-29
CN108066774A (zh) 2018-05-25
US20200268705A1 (en) 2020-08-27
EP3698812A4 (en) 2021-06-30
CN113559277B (zh) 2023-11-17

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