WO2018059193A1 - 一种稳定的重组人血管内皮抑制素皮下注射组合物 - Google Patents

一种稳定的重组人血管内皮抑制素皮下注射组合物 Download PDF

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WO2018059193A1
WO2018059193A1 PCT/CN2017/100364 CN2017100364W WO2018059193A1 WO 2018059193 A1 WO2018059193 A1 WO 2018059193A1 CN 2017100364 W CN2017100364 W CN 2017100364W WO 2018059193 A1 WO2018059193 A1 WO 2018059193A1
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recombinant human
human endostatin
concentration
injection
prescription
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PCT/CN2017/100364
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French (fr)
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李玲
许向阳
赵群
姜桂香
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山东先声生物制药有限公司
江苏先声药业有限公司
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    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • 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
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the technical field of recombinant human endostatin pharmaceutical compositions.
  • Recombinant human endostatin (rhEndostatin, Chinese name: (ZL 00107569.1) is a nucleotide coding sequence of human endostatin that has 9 additional amino acid sequences at its N-terminus.
  • the recombinant human endostatin produced is composed of 192 amino acids, and its amino acid sequence is: (M) GGSHHHHHHSHRDFQPVLHLVALNSPLSGGMRGIRGADFQCFQQARAVGLAGTFRAFLSSRLQDLYSIVRRADRAAVPIVNLKDELLFPSWEALFSGSEGPLKPGARIFSFDGKDVLRHPTWPQKSVWHGSDPNGRRLTESYCETWRTEAPSATGQASSLLGGRLLGQSAASCHHAYIVLCIENSFMTASK.
  • the recombinant human endostatin is commercially available as an ordinary injection.
  • the patient needs to be injected once a day for 14 consecutive days, and after one week of rest, the next course of treatment is continued.
  • the intravenous infusion time is at least 3 to 4 hours, and the patient's clinical compliance is poor. Therefore, the development of recombinant human endostatin into a subcutaneous injection preparation can replace the traditional intravenous infusion solution, significantly shorten the administration time, reduce the physiological pain of the patient, and improve the clinical compliance of the patient.
  • the domestically produced recombinant human endostatin injection is administered intravenously with a specification of 15 mg/3 mL. If a subcutaneous injection is developed, the concentration should be increased to 15 mg/1 mL to 15 mg/0.5 mL.
  • the increase in recombinant human endostatin concentration is accompanied by a significant increase in visible foreign bodies or particles, and there is no recombinant human endostatin subcutaneous injection in the country.
  • the technical problem to be solved by the present invention is to provide a recombinant human endostatin subcutaneous injection composition having high concentration and stability.
  • the inventors have, after extensive experimentation, surprisingly found that the combination of a saccharide and a surfactant in a buffer system of a specific pH can significantly inhibit the formation of foreign bodies or particles visible in recombinant human endostatin at a high concentration.
  • the recombinant human endostatin subcutaneous injection composition of the present invention comprises a stabilizer, a buffer solution and recombinant human endostatin.
  • the stabilizer according to the present invention means that the formation of foreign matter or particles which can be inhibited by recombinant human endostatin at a high concentration can be inhibited.
  • Stabilizers in the compositions include saccharides and surfactants.
  • the saccharide is preferably one or more of sucrose, lactose, glucose, trehalose, mannitol, and sorbitol, and more preferably one or more of trehalose, mannitol, and sucrose.
  • the saccharide has a concentration of 10 to 100 mg/ml, and is further selected from 20 to 80 mg/ml, preferably 40 mg/ml.
  • the surfactant is preferably one or more of polysorbate and poloxamer.
  • polysorbate is preferably one or more of Tween 20 and Tween 80.
  • poloxamer is preferably poloxamer 105, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 401, poloxamer 403, mooring One or more of Lohsam 407, more preferably one or both of poloxamer 188, poloxamer 407.
  • the surfactant is used in an amount of from 0.1 to 2 mg/ml, preferably from 0.2 to 2 mg/ml.
  • the concentration described above is calculated based on the volume of the injection solution.
  • the buffer solution is preferably an acetate buffer solution or a histidine buffer solution, preferably an acetic acid-sodium acetate buffer or a histidine-histidine hydrochloride buffer.
  • the buffer system preferably has a pH of from 5.0 to 6.5, preferably from 5.0 to 6.0.
  • the buffer system concentration is preferably 20 mM to 120 mM, preferably 20 mM to 60 mM.
  • the recombinant human endostatin of the present invention is a protein, a fragment or a modified form thereof capable of inhibiting proliferation of endothelial cells.
  • the recombinant human endostatin may be a liquid, or may be a freeze-dried, or spray-dried solid.
  • the recombinant human endostatin is rhEndostatin (Endostar), and the recombinant human endostatin concentration is 15 mg/mL to 30 mg/mL.
  • the first composition of the present invention uses a combination of a saccharide and a surfactant as a stabilizer, and can significantly inhibit the formation of foreign bodies or granules of recombinant human endostatin at a high concentration in a buffer system of a specific pH, thereby improving stability. ;
  • the subcutaneous injection of the present invention significantly shortens the administration time, reduces the physiological pain of the patient, and improves the clinical compliance of the patient as compared with the conventional intravenous drip.
  • the human body has a pH of 7.4, and the pH of the injection is generally required to be between 4 and 9.
  • the pH of the injection is generally required to be between 4 and 9.
  • the inventors separately prepared the solution according to Table 1, and potted in a vial for storage, wherein the buffer system is The acetate buffer is acetic acid-sodium acetate buffer, the citrate buffer is sodium citrate-sodium citrate buffer, and the histidine buffer is histidine-histidine hydrochloride buffer.
  • the phosphate buffer is sodium dihydrogen phosphate-disodium hydrogen phosphate buffer.
  • Accelerated experiments were carried out at 25 ° C for 2 weeks, 40 ° C for 2 weeks, and 40 ° C for 4 weeks. The appearance and purity of the above prescriptions were examined.
  • the purity of rhEndostatin was determined by HPLC.
  • the column of HPLC method was C 18 reverse phase column, the aqueous solution of 0.1% trifluoroacetic acid was used as mobile phase A solution, and the acetonitrile of 0.1% trifluoroacetic acid was used as mobile phase B.
  • the solution was eluted for 24 min (from 64% to 40% for solution A and from 36% to 60% for solution B) at a flow rate of 1.3 ml/min and a detection wavelength of 214 nm.
  • Placement condition Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6 Prescription 7 Prescription 8 0 days 98.60 98.74 98.57 98.67 98.63 98.57 98.55 98.56 25°C for 2 weeks 98.65 98.69 98.45 98.54 98.60 98.59 98.50 98.44 40 ° C for 2 weeks 97.64 97.87 ND* ND* 97.74 97.98 ND* ND* 40 ° C for 4 weeks 92.78 93.91 ND* ND* 92.84 ND* ND* ND*
  • ND* Indicates that no measurement has been taken.
  • the buffer systems having a pH of 5.0 to 6.5 have good stability at room temperature of 25 ° C.
  • the buffer solution is acetate buffer
  • the highest stability is exhibited during the accelerated test, and there is no obvious change in appearance at 40 ° C for 4 weeks; however, when the buffer solution is histidine, it is stable.
  • the difference in pH depends on the pH value; when the buffer solution is citrate buffer and phosphate, there is visible foreign matter at 40 ° C for 2-4 weeks, ie, flaky protein is precipitated, the stability of the system is not high.
  • the acetate buffer system and histidine buffer system were used to study the effects of carbohydrates and surfactants on the stability of recombinant human endostatin.
  • the inventors prepared solutions according to Table 4 and potted in Xilin. Store in a bottle.
  • the acetate buffer is acetic acid-sodium acetate buffer
  • the histidine buffer is histidine-histidine hydrochloride buffer
  • the phosphate buffer is sodium dihydrogen phosphate- Disodium hydrogen phosphate buffer.
  • Prescription 9 Prescription 10
  • Prescription 11 Prescription 12
  • Prescription 13 Recombinant human endostatin 30mg 15mg 30mg 15mg 30mg Mannitol 40mg 60mg - - 40mg Trehalose - - 20mg - -
  • the purity of rhEndostatin was determined by HPLC.
  • the column of HPLC method was C 18 reverse phase column, the aqueous solution of 0.1% trifluoroacetic acid was used as mobile phase A solution, and the acetonitrile of 0.1% trifluoroacetic acid was used as mobile phase B.
  • the solution was eluted for 24 min (from 64% to 40% for solution A and from 36% to 60% for solution B) at a flow rate of 1.3 ml/min and a detection wavelength of 214 nm.
  • Placement condition Prescription 9
  • Prescription 10 Prescription 11
  • Prescription 12 Prescription 13 0 days 99.72 99.68 99.70 99.71 99.71
  • the particle size was measured by the DLS method (dynamic light scattering method) using a Malvern Zetasizer nano Z-type laser detector. The results are shown in Table 7:
  • Placement condition Prescription 9
  • Prescription 10 Prescription 11
  • Prescription 12 Prescription 13 0 days 3.73 3.83 4.87 4.62 6.27 40 ° C for 2 weeks 3.66 3.66 5.04 4.59 10.52 40 ° C for 4 weeks 3.84 4.02 6.51 4.25 31.96

Abstract

一种重组人血管内皮抑制素注射液，主要由稳定剂、缓冲溶液、重组人血管内皮抑制素组成。

Description

一种稳定的重组人血管内皮抑制素皮下注射组合物 技术领域
本发明涉及重组人血管内皮抑制素药物组合物技术领域。
背景技术
重组人血管内皮抑制素(rhEndostatin，
Figure PCTCN2017100364-appb-000001
中文名：
Figure PCTCN2017100364-appb-000002
)(ZL 00107569.1)是通过修饰人血管内皮抑制素的核苷酸编码序列使其N末端带有9个附加氨基酸序列。所生产的重组人血管内皮抑制素由192个氨基酸构成，其氨基酸序列为：(M)GGSHHHHHHSHRDFQPVLHLVALNSPLSGGMRGIRGADFQCFQQARAVGLAGTFRAFLSSRLQDLYSIVRRADRAAVPIVNLKDELLFPSWEALFSGSEGPLKPGARIFSFDGKDVLRHPTWPQKSVWHGSDPNGRRLTESYCETWRTEAPSATGQASSLLGGRLLGQSAASCHHAYIVLCIENSFMTASK。
O’Reilly教授于1997年从小鼠内皮细胞系EOMAD的培养液中分离得到了具有抑制血管内皮细胞生长的物质(血管内皮抑制素，Endostatin)，其通过抑制肿瘤血管的生成能够显著地抑制多种原发性肿瘤的生长(O’Relly,M.S.,et al.Cell.1997,88:277-285)。重组人血管内皮抑制素正是基于“饿死肿瘤疗法”理论来抑制肿瘤生长，临床上联合NP化疗方案用于非小细胞肺癌患者。
目前市售的重组人血管内皮抑制素为普通注射液，临床使用中患者需每天注射一次，连续14天为一个疗程，休息一周后，再继续下一疗程。而每天注射时，静脉滴注时间至少3～4h，患者临床顺应性差。因此，将重组人血管内皮抑制素开发成皮下注射制剂，可以替代传统的静脉滴注溶液，显著缩短给药时间，降低患者生理上的痛苦，提高患者的临床顺应性。
目前国内生产的重组人血管内皮抑制素注射液给药途径为静脉滴注，规格为15mg/3mL。若开发皮下注射液，需将浓度提高至15mg/1mL～15mg/0.5mL。然而重组人血管内皮抑制素浓度提高带来的是可见异物或颗粒的显著增加，国内尚无重组人血管内皮抑制素皮下注射液。
发明内容
本发明的目的是提供一种适合用作皮下注射的重组人血管内皮抑制素注射液，显著缩短给药时间，从而降低患者生理上的痛苦，提高患者的临床顺应性。
本发明所要解决的技术问题是提供一种浓度高、稳定性好的重组人血管内皮抑制素皮下注射组合物。
发明人经过大量的试验，惊奇的发现，在特定pH的缓冲体系中采用糖类与表面活性剂组合，能够显著抑制高浓度下重组人血管内皮抑制素可见异物或颗粒的形成。
本发明的重组人血管内皮抑制素皮下注射组合物包括稳定剂，缓冲溶液和重组人血管内皮抑制素。
本发明所述的稳定剂是指能够抑制重组人血管内皮抑制素在高浓度下可见异物或颗粒的形成。本组合物中稳定剂包括糖类及表面活性剂。
其中糖类优选为蔗糖、乳糖、葡萄糖、海藻糖、甘露醇、山梨醇的一种或多种，更优选的为海藻糖、甘露醇、蔗糖中的一种或多种。
优选的，所述糖类浓度为10～100mg/ml，进一步选自20～80mg/ml，优选为40mg/ml。
其中表面活性剂优选为聚山梨酯、泊洛沙姆中的一种或多种。
其中聚山梨酯优选为吐温20、吐温80中的一种或多种。
其中泊洛沙姆优选为泊洛沙姆105，泊洛沙姆124，泊洛沙姆188，泊洛沙姆237，泊洛沙姆338，泊洛沙姆401，泊洛沙姆403，泊洛沙姆407中的一种或多种，更优选的为泊洛沙姆188、泊洛沙姆407中的一种或两种。
优选的，表面活性剂用量浓度为0.1～2mg/ml，优选为0.2～2mg/ml。
以上所述的浓度是以所述注射剂液的体积为基准计算.
其中缓冲溶液优选的为醋酸盐缓冲溶液或组氨酸盐缓冲溶液，优选为醋酸-醋酸钠缓冲液或组氨酸-盐酸组氨酸缓冲液。
其中缓冲体系优选pH为5.0-6.5，优选为5.0～6.0。
其中缓冲体系浓度优选为20mM～120mM，优选为20mM～60mM。
本发明所述的重组人血管内皮抑制素是能够抑制内皮细胞增殖的蛋白质、片段或其修饰形式。重组人血管内皮抑制素可以是液体，也可以是冷冻干燥的，或者喷雾干燥的固体。优选的，重组人血管内皮抑制素为rhEndostatin(恩度，Endostar)，重组人血管内皮抑制素浓度为15mg/mL～30mg/mL。
本发明的优点主要在于：
第一本发明组合物中采用了糖类与表面活性剂组合作为稳定剂，在特定pH的缓冲体系中可以显著抑制重组人血管内皮抑制素在高浓度下可见异物或颗粒的形成，提高稳定性；
第二与传统静脉滴注相比，本发明的皮下注射剂显著缩短给药时间，降低患者生理上的痛苦，提高患者的临床顺应性。
具体实施方式
本发明通过下列实施例作更详细的描述，但本发明的保护范围不局限于此。
实施例1缓冲体系的筛选
(1)处方配制
人体pH值为7.4，一般要求注射液pH值在4～9之间。另外，为确保成品在贮藏期内药液质量稳定，需确定药液合理的pH值范围，本发明人分别按照表1配制溶液，灌封于西林瓶中贮藏，其中，所述的缓冲体系中，醋酸盐缓冲液为醋酸-醋酸钠缓冲液，枸橼酸盐缓冲液为枸橼酸-枸橼酸钠缓冲液，组氨酸盐缓冲液为组氨酸-盐酸组氨酸缓冲液，磷酸盐缓冲液为磷酸二氢钠-磷酸氢二钠缓冲液。
表1 处方列表
Figure PCTCN2017100364-appb-000003
(2)加速试验
采用加速实验，分别在25℃条件下贮藏2周、40℃条件下贮藏2周、40℃条件下贮藏4周，对以上处方的外观以及纯度进行检查。
对纯度检查时，采用HPLC测定rhEndostatin纯度，HPLC法的色谱柱为C18反相柱，以0.1％三氟乙酸的水溶液为流动相A液，以0.1％三氟乙酸的乙腈容易为流动相B液，梯度洗脱24min(A液从64％-40％，B液从36％-60％)，流速为1.3ml/min，检测波长为214nm。
外观结果如表2所示：
表2 外观观察结果
Figure PCTCN2017100364-appb-000004
Figure PCTCN2017100364-appb-000005
纯度检查结果如表3所示：
表3 HPLC纯度结果
放置条件 处方1 处方2 处方3 处方4 处方5 处方6 处方7 处方8
0天 98.60 98.74 98.57 98.67 98.63 98.57 98.55 98.56
25℃2周 98.65 98.69 98.45 98.54 98.60 98.59 98.50 98.44
40℃2周 97.64 97.87 ND* ND* 97.74 97.98 ND* ND*
40℃4周 92.78 93.91 ND* ND* 92.84 ND* ND* ND*
ND*：表示未进行测定。
由表2和表3可见，在含有甘露醇的重组人血管内皮抑制素(rhEndostatin)处方中，在25℃室温条件下，pH为5.0～6.5的各缓冲体系都有较好的稳定性。当缓冲溶液为醋酸盐缓冲液时，在加速试验过程中体现出最高的稳定性，在40℃下保存4周外观上也无明显变化；但当缓冲溶液为组氨酸盐时，其稳定性据pH值不同而有所不同；当缓冲溶液为而枸橼酸盐缓冲液和磷酸盐时，则在40℃下2-4周时有可见异物即有片状蛋白析出，体系稳定性不高。
实施例2稳定剂糖类及表面活性剂的影响
(1)处方配制
选用醋酸盐缓冲体系及组氨酸盐缓冲体系，研究糖类及表面活性剂对重组人血管内皮抑制素(rhEndostatin)稳定性的影响，本发明人分别按照表4配制溶液，灌封于西林瓶中贮藏。其中，所述的缓冲体系中，醋酸盐缓冲液为醋酸-醋酸钠缓冲液，组氨酸盐缓冲液为组氨酸-盐酸组氨酸缓冲液，磷酸盐缓冲液为磷酸二氢钠-磷酸氢二钠缓冲液。
表4 处方列表
成分 处方9 处方10 处方11 处方12 处方13
重组人血管内皮抑制素 30mg 15mg 30mg 15mg 30mg
甘露醇 40mg 60mg — — 40mg
海藻糖 — — 20mg — —
蔗糖 — — — 80mg —
聚山梨酯(吐温80) 0.2mg — — — 0.2mg
聚山梨酯(吐温20) — 2mg — — —
泊洛沙姆(188) — — 0.1mg — —
泊洛沙姆(407) — — — 0.5mg —
pH5.0、30mM醋酸盐缓冲液 1mL — 1mL — —
pH6.0、20mM组氨酸盐缓冲液 — 1mL — 1mL —
pH5.0、30mM磷酸盐缓冲液 — — — — 1mL
(2)加速试验
采用加速实验，分别在25℃条件下贮藏2月、25℃贮藏条件下6月、40℃条件下贮藏2周、40℃条件下贮藏4周，对以上处方的外观以及纯度进行检查。
对纯度检查时，采用HPLC测定rhEndostatin纯度，HPLC法的色谱柱为C18反相柱，以0.1％三氟乙酸的水溶液为流动相A液，以0.1％三氟乙酸的乙腈容易为流动相B液，梯度洗脱24min(A液从64％-40％，B液从36％-60％)，流速为1.3ml/min，检测波长为214nm。
外观观察结果如表5所示：
表5 外观观察结果
Figure PCTCN2017100364-appb-000006
纯度检查结果如表6所示：
表6 HPLC纯度结果
放置条件 处方9 处方10 处方11 处方12 处方13
0天 99.72 99.68 99.70 99.71 99.71
25℃2月 98.56 98.67 98.57 98.58 98.59
25℃6月 98.55 98.60 98.47 98.57 98.51
40℃2周 98.17 98.18 98.20 98.22 98.08
40℃4周 97.00 97.11 97.15 97.02 94.68
使用马尔文公司Zetasizer nano Z型激光检测仪，采用DLS法(动态光散射法)测定粒径，结果如表7所示：
表7 DLS结果(平均粒径，nm)
放置条件 处方9 处方10 处方11 处方12 处方13
0天 3.73 3.83 4.87 4.62 6.27
40℃2周 3.66 3.66 5.04 4.59 10.52
40℃4周 3.84 4.02 6.51 4.25 31.96
由表5、表6、表7可见，采用醋酸盐缓冲体系及组氨酸盐缓冲体系，处方中加入糖类如蔗糖、甘露醇、海藻糖，同时加入一定浓度的表面活性剂如吐温或泊洛沙姆，在特定pH的缓冲体系中可以显著抑制重组人血管内皮抑制素在高浓度下(15mg/ml～30mg/ml)可见异物或颗粒的形成，具有很高的稳定性。

Claims (12)

  1. 一种重组人血管内皮抑制素注射液，其特征在于该注射液主要由以下组分组成：
    a)稳定剂；
    b)缓冲溶液；
    c)重组人血管内皮抑制素。
  2. 根据权利要求1所述的注射液，其特征在于所述稳定剂主要由糖类和表面活性剂组成。
  3. 根据权利要求2所述的注射液，其特征在于所述糖类选自蔗糖、乳糖、葡萄糖、海藻糖、甘露醇、山梨醇中的一种或多种，优选的选自海藻糖、甘露醇、蔗糖中的一种或多种，进一步优选自甘露醇。
  4. 根据权利要求2所述的注射液，其特征在于所述糖类浓度为10～100mg/ml，进一步选自20～80mg/ml，优选为40mg/ml。
  5. 根据权利要求2所述的注射液，其特征在于所述表面活性剂选自聚山梨酯、泊洛沙姆中的一种或多种，其中所述的聚山梨酯选自吐温20、吐温80中的一种或多种。
  6. 根据权利要求2所述的注射液，其特征在于所述表面活性剂浓度为0.1～2mg/ml，优选为0.2～2mg/ml。
  7. 根据权利要求1所述的注射液，其特征在于所述的缓冲溶液为醋酸盐缓冲溶液或组氨酸盐缓冲溶液，进一步优选为醋酸-醋酸钠缓冲液。
  8. 根据权利要求1所述的注射液，其特征在于所述的缓冲溶液浓度为20mM～120mM，优选为20mM～60mM。
  9. 根据权利要求1所述的注射液，其特征在于所述缓冲溶液的pH值为5.0-6.5，优选为5.0～6.0。
  10. 根据权利要求1～11任一项所述的注射液，其特征在于所述的重组人血管内皮抑制素的浓度为15～30mg/ml。
  11. 根据权利要求1～11任一项所述的注射液，其特征在于所述的重组人血管内皮抑制素为rhEndostatin。
  12. 一种重组人血管内皮抑制素注射液，其特征在于该注射液主要由以下组分组成：
    a)浓度为40mg/ml的甘露醇和浓度为0.2-2mg/ml的吐温80；
    b)pH值为5.0-6.0、浓度为30mM的醋酸-醋酸钠缓冲液；
    c)rhEndostatin。
PCT/CN2017/100364 2016-09-28 2017-09-04 一种稳定的重组人血管内皮抑制素皮下注射组合物 WO2018059193A1 (zh)

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CN103083681A (zh) * 2006-01-20 2013-05-08 清华大学 一种治疗肿瘤的药物及其应用
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* Cited by examiner, † Cited by third party
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