WO2019129278A1 - 培化西海马肽的药物组合物及其制备方法 - Google Patents

培化西海马肽的药物组合物及其制备方法 Download PDF

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WO2019129278A1
WO2019129278A1 PCT/CN2018/125599 CN2018125599W WO2019129278A1 WO 2019129278 A1 WO2019129278 A1 WO 2019129278A1 CN 2018125599 W CN2018125599 W CN 2018125599W WO 2019129278 A1 WO2019129278 A1 WO 2019129278A1
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buffer
pharmaceutical composition
cultured
peptide
injection
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PCT/CN2018/125599
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English (en)
French (fr)
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孙运栋
胡迪
陈国辉
张丰盈
闫智颖
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江苏豪森药业集团有限公司
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Priority to CN201880007454.8A priority Critical patent/CN110214019B/zh
Publication of WO2019129278A1 publication Critical patent/WO2019129278A1/zh

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    • 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
    • A61K38/18—Growth factors; Growth regulators
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates to the field of polypeptide pharmaceutical preparations.
  • the present invention relates to a pharmaceutical preparation comprising a cultured dipamapeptide and a process for the preparation thereof.
  • Peihua Xihaima peptide is a polyethylene glycol modified erythropoietin mimetic peptide derivative, in which EPO acts on bone marrow hematopoietic cells, stimulates mitosis and differentiation of erythroid precursor cells, promotes proliferation and differentiation of erythrocyte stem cells, and finally matures into Endocrine hormones. Because EPO is essential in the process of red blood cell formation, it can promote red blood cell proliferation, increase the body's total hemoglobin (Hb), improve the body's oxygen carrying capacity, so the hormone in the diagnosis and treatment of erythropoiesis or red blood cell defects There are a wide range of applications in the disease.
  • Hb body's total hemoglobin
  • anemia of myelodysplastic syndrome can also be used for autologous blood transfusion before surgery and recovery of anemia after surgery, anemia of myelodysplastic syndrome, sickle cell anemia of hemoglobin disease, ⁇ -thalassemia, anemia of premature infants, chronic inflammation or anemia caused by infection, Spinal cord injury, renal anemia, aplastic anemia, etc.
  • Peihua Xihai Mapeptide is a product of EPO mimetic peptide modified by PEGylation. It belongs to chemically synthesized peptide drugs and is clinically used to treat anemia caused by renal failure.
  • the cultured Xihaima peptide has good water solubility, poor thermal stability, and is easily digested in the gastrointestinal tract. Therefore, clinically, the administration form of the cultured Xihaima peptide is an injection or a lyophilized powder, preferably an injection.
  • the object of the present invention is to provide a stable cultured composition of ximarin peptide, which can significantly control polymer impurities, and has a simple formulation, safe and effective formulation, greatly improves the metabolism behavior of the cultured Xihaima peptide, and prolongs the action time. .
  • the present invention is mainly implemented by the following schemes:
  • the cultured Xihai Mapeptide pharmaceutical composition comprises an active ingredient for culturing xihai horse peptide, a buffer solution and an isotonicity regulating agent, and the structure of the cultured Xihai Mapeptide is:
  • n is selected from the group consisting of 400-600, preferably 455.
  • the cultured medicinal composition of the present invention may be administered orally or by injection, and the injection method includes subcutaneous injection, intramuscular injection or intravenous drip.
  • the concentration of the cultured di-hepatic peptide is selected from the group consisting of 0.1 mg/ml to 100 mg/ml, preferably 0.1 mg/ml to 20 mg/ml, more preferably 2 mg/ml, 4 mg/ml or 6 mg/ml.
  • the cultured Xihai Mapeptide composition is a Peihuama peptide injection containing 0.05% to 5.0% (W/V) of the cultured di-hormone peptide, 0.1% to 5.0% (W/V). Buffer salt, 0.05% to 5.0% (w/v) isotonicity regulator.
  • W/V the cultured Xihai Mapeptide composition
  • Buffer salt 0.05% to 5.0% (w/v) isotonicity regulator.
  • the unit of W/V is g/mL.
  • the cultured di-horse peptide injection comprises 0.1% to 2% (w/v) of peminated hippocampus, 0.3% to 3.0% (w/v) of buffer salt, 0.1% to 2.0% ( Isotonicity regulator for W/V).
  • the cultured Xihai Mapeptide injection comprises 0.1% to 1.0% (w/v) of the cultured di-hepatic peptide, 0.5% to 1.5% (w/v) of the buffer salt, 0.1% to 1.0% ( Isotonicity regulator for W/V).
  • the buffer is selected from the group consisting of phosphate buffer, acetate buffer, citrate buffer, carbonate buffer, tartrate buffer, Tris buffer, histidine, preferably acetic acid.
  • the phosphate buffer solution includes dihydrogen phosphate salt and dibasic hydrogen phosphate.
  • the isotonicity adjusting agent is selected from one or more of sodium chloride, mannitol, sorbitol, glycerol, glucose, xylitol, preferably mannitol or sodium chloride.
  • the cultured Xihai Mapeptide injection comprises 0.1% to 2% (w/v) of peminated horse-horm peptide, 0.1% to 2.0% (w/v) of dihydrogen phosphate, 0.1% to 2.0. % (W/V) of dibasic hydrogen phosphate, 0.1% to 2.0% (w/v) of sodium chloride; preferably, the cultured di-hormone injection comprises 0.1% to 1% (W/V) Cultured Xihai Mapeptide, 0.2% to 1% (w/v) dihydrogen phosphate, 0.1% to 0.6% (w/v) dibasic hydrogen phosphate, 0.1% to 1.0% (W/V) Sodium chloride, where the unit of W/V is g/mL.
  • the weight ratio of the cultured di-hormone to the buffer salt is from 1:1 to 10, preferably from 1:2 to 4.
  • the buffer salt has a weight ratio of a base to an acid of from 1:1 to 10, preferably from 1:1 to 5. Further preferably, the buffer salt is selected from the group consisting of sodium dihydrogen phosphate and disodium hydrogen phosphate in a weight ratio of from 1 to 10:1, preferably from 1 to 3:1, more preferably from 1.2 to 2:1.
  • the weight ratio of the cultured di-hormone to the isotonicity adjusting agent is 1:0.5 to 10, preferably 1:1 to 2.
  • the weight ratio of the cultured di-hormone peptide, buffer salt and isotonicity adjusting agent is 1:1 to 10:0.5 to 10, preferably 1:2 to 4:1 to 2, more preferably 1:2.8:1.
  • the weight ratio of sodium dihydrogen phosphate and disodium hydrogen phosphate in the buffer salt is 1.6:1.
  • the pharmaceutical composition has a pH in the range of 4.0 to 7.0, preferably 5.0 to 6.0.
  • a further object of the present invention is to provide a method for preparing the pharmaceutical composition, dissolving a buffer salt and an isotonicity adjusting agent in water for injection, adding activated carbon, filtering and decarbonizing to obtain an intermediate drug solution; and dissolving the cultured Xihai Mapeptide to The above chemical solution is stirred and dissolved, filtered, and dispensed.
  • the low temperature condition is between 2 ° C and 25 ° C.
  • the pharmaceutical composition is prepared by sterile filtration, dispensing, and nitrogen filling.
  • the intermediate drug solution is formulated with nitrogen gas.
  • the intermediate solution is subjected to nitrogen pressure filtration.
  • the filling process is done under nitrogen protection.
  • the pharmaceutical composition is dispensed using a vial.
  • the pharmaceutical composition is dispensed using a bottle.
  • the pharmaceutical composition is dispensed using a prefilled syringe.
  • a maintenance dose of kg is used to maintain hemoglobin in the range of 10.0-12.0 g/dL.
  • the patient is given an initial dose of 0.02-0.10 mg/kg, and thereafter a maintenance dose of 0.015-0.15 mg/kg is administered every 26-30 days to maintain hemoglobin in the range of 10.0-12.0 g/dL.
  • a method of treating anemia is provided, the patient is administered an initial dose of 0.02-0.10 mg/kg, and thereafter a maintenance dose of 0.015-0.15 mg/kg is administered every 28 days to maintain hemoglobin in the range of 10.0-12.0 g/dL. Inside.
  • the anemia caused by chronic renal failure is treated.
  • the dosage adjustment method is as follows:
  • the red blood cell increased by ⁇ 1.0g/dL within 4 weeks after administration, and the hemoglobin ⁇ 9.0g/dL was up-regulated by 40%-60%.
  • the red blood cell increased by ⁇ 1.0g/dL within 4 weeks after administration, and 9.0g/dL ⁇ hemoglobin ⁇ 10.0g/dL, which needs to be adjusted by 20%-30%.
  • the red blood cell increased by ⁇ 1.0g/dL within 2 weeks after administration, or increased by ⁇ 2.0g/dL within 4 weeks, and it should be lowered by 20%-30%.
  • Hemoglobin ⁇ 13.0g / dL need to be suspended until hemoglobin ⁇ 12.0g / dL.
  • the polymer impurity is a polymer of fermented dipamapeptide, and the presence of the impurity degrades the product and lowers the content of the product.
  • the invention can obtain a stable and stable cultured Xihaima peptide pharmaceutical composition by screening the components in the prescription, by controlling the proportion of each component, without adding other auxiliary materials, and can effectively control the culture of Xihai Mapeptide. Polymer impurities.
  • Diluent Water for the test solution Take about 25mg of this product, put it in a 5ml volumetric flask, add water to dissolve and dilute to the mark, shake well.
  • control solution was accurately weighed 1 ml of the test solution, placed in a 100 ml volumetric flask, diluted with water to the mark, and shaken.
  • a i ------ when calculating the polymer is the sum of the peak areas of the polymer in the chromatogram of the test solution (the peak whose peak is earlier than EPO-018B is the peak of the polymer);
  • the retention time is 8.2 min.
  • Figure 1 shows the time change of hemoglobin (Hgb) and reticulocyte (Ret) in the subcutaneous injection of 100 ⁇ g.kg -1 .
  • Figure 2 shows the time change of hemoglobin (Hgb) and reticulocyte (Ret) in the subcutaneous injection of 500 ⁇ g.kg -1 .
  • Figure 3 shows the time change of hemoglobin (Hgb) and reticulocyte (Ret) in subcutaneous injection of 1500 ⁇ g.kg -1 .
  • FIG. 4 is a cynomolgus 100 ⁇ g.kg -1 intravenous dose, hemoglobin (Hgb) and reticulocyte (Ret) time
  • Test object
  • Test article the cultured Xihaima peptide injection prepared in Example 3-5;
  • Preparation of blood cell suspension Take 5 ml of canine blood, stir the blood with a glass rod, remove fibrinogen, and make it defibrillated blood. Add about 10 times the amount of 0.9% sodium chloride solution, shake well, centrifuge at 1500 rpm for 15 minutes, remove the supernatant, and precipitate the red blood cells and wash them 3 times with 0.9% sodium chloride solution as above, until the supernatant is not It is red. The blood cell 1.0 ml was weighed and diluted with physiological saline to 50 ml to prepare a 2% suspension for testing.
  • Example 4 of Example 3 was diluted with physiological saline to 1.00 mg/ml, and mixed for use.
  • Test 1 and Test 2 8 tubes were taken separately, and various solutions were added in the following order.
  • the first to fifth tubes are the test tube, the sixth tube is the negative control tube, the seventh tube is the positive control tube, and the eighth tube is the vehicle control tube.
  • the tubes were gently shaken, placed in a 37 ° C water bath, and the results of 15 min, 30 min, 45 min, 1 h, 2 h, 3 h were observed and recorded. Take pictures at each observation time. If the solution becomes clear and stained red, it means hemolysis. If necessary, the microscope can be used to observe whether the red blood cells are broken.
  • Test 2 shows that the cultured Xihaima peptide injection prepared by the present invention is safe, and does not have an allergic reaction to nerve, cardiovascular, respiratory and subcutaneous tissues.
  • Test Example 3 Pharmacokinetics and pharmacodynamics of macaque after subcutaneous or intravenous injection of Xihai Mapeptide
  • Rhesus macaques were injected subcutaneously with the cultured mepetic peptides prepared in Example 3 (100, 500 and 1500 g.kg -1 , low, medium and high doses).
  • the end phase half-life t 1/2 increased with dose between each dose group.
  • the systemic clearance rate CL gradually decreased with increasing dose, suggesting that the drug exhibited nonlinear pharmacokinetic characteristics in rhesus monkeys in the range of 100-1500 g.kg -1 .
  • the serum antigen concentration of the macaque was 1008. ⁇ 999.5 ng.mL -1 2 minutes after intravenous injection of 100 g.kg -1 of the cultured pehemin peptide prepared in Example 3. The serum antigen concentration was reduced to 72 hours after administration. Background level.
  • AUC(0-t) was 19385 ⁇ 758.6 (ng ⁇ h) mL -1 , (P ⁇ 0.001 vs sc 100 ⁇ g.kg -1 ), and AUC(0- ⁇ ) was 207020 ⁇ 758.6 (ng ⁇ h) mL -1 (P ⁇ 0.001 vs sc 100 ⁇ g. kg -1 ), there was a statistically significant difference compared to the isodose sc group.
  • the terminal phase half-life t 1/2 ⁇ was 17.4 ⁇ 0.6h, which was statistically significant compared with sc100 ⁇ g.kg -1 (P ⁇ 0.01), and the systemic clearance CL was 5.0 ⁇ 0.2mL.h -1 .kg -1 .
  • reticulocyte Compared with pre-dose, Peihuama peptide stimulated the synthesis of reticulocyte (Ret) in a dose-dependent manner, and the reticulocytes on the 6th day were increased by the subcutaneous injection of 100 and 500 g.kg -1 in the dose group.
  • the doses from the 3 dose groups to 45 days did not fall to the pre-dose level.
  • Rhesus macaques were injected subcutaneously with the cultured Xihaima peptide of Example 5 for 4 weeks.
  • the peak times after the first week and the fourth week were 20 ⁇ 6.9h and 12.0 ⁇ 0.0h, respectively; the peak concentration Cmax was 2408.8 ⁇ 262.3.
  • Ng ⁇ mL-1 and 2346.1 ⁇ 247.6 ng ⁇ mL-1, the terminal phase half-life T 1/2 ⁇ were 31.2 ⁇ 5.6 h and 30.1 ⁇ 3.8 h, respectively.

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Abstract

本发明涉及培化西海马肽的药物组合物及其制备方法。本发明公开了一种以培化西海马肽为活性成分的药物组合物。所述药物组合物含有培化西海马肽、pH值为3.0-7.0的生理可接受缓冲液和药学上可接受辅料。本发明药物组合物具有良好的药物稳定性和安全性，并且制备方法简便，适合工业化生产。

Description

培化西海马肽的药物组合物及其制备方法 技术领域
本发明涉及多肽类药物制剂领域。具体而言，本发明涉及包含培化西海马肽的药物制剂及其制备方法。
背景技术
培化西海马肽是聚乙二醇修饰的促红细胞生成素模拟肽衍生物，其中EPO作用于骨髓造血细胞，刺激有丝分裂和红细胞前体细胞的分化，促进红细胞系干细胞增生、分化，最终成熟为内分泌激素。由于EPO在血红细胞形成过程中是必需的，它能促使红细胞增生，提高机体的血红蛋白(Hb)总量，改善机体携氧能力，所以该激素在诊断和治疗红细胞生成不足或红细胞产生缺陷的血液疾病中有着广泛的应用。此外，也可用于外科手术前的自体输血及手术后贫血的恢复、骨髓异常增生综合征贫血、血红蛋白病的镰状红细胞贫血及β-地中海贫血、早产儿贫血、慢性炎症或感染引起的贫血、脊髓损伤、肾性贫血、再生障碍性贫血等等。
培化西海马肽是EPO模拟肽经聚乙二醇化修饰后的产物，属于化学合成的多肽类药物，临床上拟用于治疗肾衰竭引起的贫血。培化西海马肽的水溶性良好，热稳定性较差，且极易在胃肠道被酶解。因此在临床上，培化西海马肽的给药剂型采用注射液或冻干粉针，优选注射液。
发明内容
本发明的目的在于提供一种稳定的培化西海马肽药物组合物，能够显著地控制聚合物杂质，同时制剂处方简单，安全有效，大大提高了培化西海马肽体内代谢行为，延长作用时间。
具体而言，本发明主要通过以下方案实施：
培化西海马肽药物组合物包括活性成分培化西海马肽、缓冲液和等渗调节剂，培化西海马肽的结构为：
Figure PCTCN2018125599-appb-000001
n选自400-600，优选455。
本发明所述的培化西海马肽药物组合物可通过口服或注射方式给药，注射方式包括皮下注射、肌肉注射或静脉滴注。
优选地，所述培化西海马肽的浓度选自0.1mg/ml～100mg/ml，优选0.1mg/ml～20mg/ml，更优选2mg/ml、4mg/ml或6mg/ml。
优选地，所述培化西海马肽组合物为培化西海马肽注射液，其包含0.05％～5.0％(W/V)的培化西海马肽，0.1％～5.0％(W/V)的缓冲盐，0.05％～5.0％(W/V)的等渗调节剂。其中W/V的单位为g/mL。
优选地，所述培化西海马肽注射液包含0.1％～2％(W/V)的培化西海马肽，0.3％～3.0％(W/V)的缓冲盐，0.1％～2.0％(W/V)的等渗调节剂。
优选地，所述培化西海马肽注射液包含0.1％～1.0％(W/V)的培化西海马肽，0.5％～1.5％(W/V)的缓冲盐，0.1％～1.0％(W/V)的等渗调节剂。
优选地，所述缓冲液选自磷酸盐缓冲液、醋酸盐缓冲液、枸橼酸盐缓冲液、碳酸盐缓冲液、酒石酸盐缓冲液、Tris缓冲液、组氨酸盐，优选醋酸盐缓冲液或磷酸盐缓冲液。其中磷酸盐缓冲液包括磷酸二氢盐和磷酸氢二盐。
优选地，所述等渗调节剂选自氯化钠、甘露醇、山梨醇、甘油、葡萄糖、木糖醇的一种或多种，优选甘露醇或氯化钠。
优选地，所述培化西海马肽注射液包含0.1％～2％(W/V)的培化西海马肽，0.1％～2.0％(W/V)的磷酸二氢盐，0.1％～2.0％(W/V)的磷酸氢二盐，0.1％～ 2.0％(W/V)的氯化钠；优选的，所述培化西海马肽注射液包含0.1％～1％(W/V)的培化西海马肽，0.2％～1％(W/V)的磷酸二氢盐，0.1％～0.6％(W/V)的磷酸氢二盐，0.1％～1.0％(W/V)的氯化钠，其中W/V的单位为g/mL。
优选地，所述培化西海马肽与缓冲盐的重量比为1:1～10，优选1:2～4。
优选地，所述缓冲盐中其碱和酸的重量比为1:1～10，优选1:1～5。进一步优选地，所述缓冲盐选自磷酸二氢钠和磷酸氢二钠，重量比为1～10：1，优选1～3：1，更优选1.2～2：1。
优选地，所述培化西海马肽与等渗调节剂的重量比为1:0.5～10，优选1:1～2。
优选地，所述培化西海马肽、缓冲盐与等渗调节剂的重量比为1:1～10：0.5～10，优选1:2～4:1～2，更优选1：2.8：1，其中缓冲盐中磷酸二氢钠和磷酸氢二钠的重量比为1.6：1。
优选地，所述药物组合物的pH范围为4.0至7.0，优选5.0至6.0。
本发明的又一目的在于提供制备所述药物组合物的方法，将缓冲盐和等渗调节剂溶于注射用水，加入活性炭，过滤脱炭得中间体药液；将培化西海马肽溶解至上述药液，搅拌溶解，过滤、分装。
优选地，所述低温条件为在2℃～25℃之间。
优选地，制备药物组合物经无菌过滤、分装、充氮气封装。
优选地，中间体药液配制采用充氮气保护。
优选地，中间体药液采用氮气压滤。
优选地，灌装过程在氮气保护下完成。
优选地，所述的药物组合物，采用西林瓶进行分装。
优选地，所述的药物组合物，采用卡式瓶进行分装。
优选地，所述的药物组合物，采用预灌封注射器进行分装。
本发明的又一目的在于提供一种治疗以缺乏红细胞生成素或红细胞群缺少或缺陷疾病的方法，给予患者0.02-0.10mg/kg的初始计量，此后每26-30天给予0.015-0.15mg/kg的维持剂量，以维持血红蛋白在10.0-12.0g/dL的范围内。
优选地，给予患者0.02-0.10mg/kg的初始计量，此后每26-30天给予0.015-0.15mg/kg的维持剂量，以维持血红蛋白在10.0-12.0g/dL的范围内。
优选地，提供一种治疗贫血的方法，给予患者0.02-0.10mg/kg的初始计量，此后每28天给予0.015-0.15mg/kg的维持剂量，以维持血红蛋白在10.0-12.0g/dL的范围内。
优选地，治疗慢性肾功能衰竭所致的贫血症。
剂量调整方式如下：
给药后4周内血红细胞升高≤1.0g/dL,且血红蛋白＜9.0g/dL需上调40％-60％。
给药后4周内血红细胞升高≤1.0g/dL,且9.0g/dL≤血红蛋白≤10.0g/dL,需上调20％-30％。
给药后2周内血红细胞升高≥1.0g/dL,或4周内升高≥2.0g/dL,需下调20％-30％。
12.0g/dL＜血红蛋白＜13.0g/dL,需下调20％-30％。
血红蛋白≥13.0g/dL,需暂停给药，直至血红蛋白≤12.0g/dL。
除以上情况外，给药剂量维持不变。
聚合物杂质是培化西海马肽的多聚体，该杂质的存在使产品降解，降低产品的含量。本发明通过处方中组分的筛选，通过对各组分比例的控制，无需添加其他辅料，即可得到稳定性好的培化西海马肽药物组合物，能够有效地控制培化西海马肽的聚合物杂质。
本发明的又一目的在于提供多聚体杂质的检测方法，步骤如下：
仪器与试剂 高效液相色谱仪、电子天平、pH计、电子分析天平、氢氧化钠(AR)、磷酸二氢钠(AR)、磷酸氢二钠(AR)、乙腈。
色谱条件 色谱柱填料：凝胶色谱柱(Shodex KW-803 300×7.8mm)；流速：0.8ml/min；检测波长：220nm；柱温：40℃；进样量：50μl。
流动相 pH为6.8的0.1mol/L的磷酸盐缓冲液：乙腈＝60：40。
稀释液：水供试品溶液取本品约25mg，置5ml量瓶中，加水溶解并稀释至刻度，摇匀。
对照溶液 精密量取供试品溶液1ml，置100ml量瓶中，加水稀释至刻度，摇匀。
系统适用性试验 精密量取空白溶液40μl，注入液相色谱仪，记录色谱图；精密量取供试品溶液40μl，注入液相色谱仪，记录色谱，理论板数按培化西海马肽计应≥1000。
聚合物测定 精密量取对照溶液40μl注入液相色谱仪，调节检测灵敏度，使主成分色谱峰的峰高为满量程的20％～30％；再精密量取供试品溶液和对照溶液各40μl，分别注入液相色谱仪，记录色谱图，供试品溶液色谱图中如显聚合物峰，按下式计算：
Figure PCTCN2018125599-appb-000002
式中：A i------计算聚合物时为供试品溶液色谱图中聚合物的峰面积的和(出峰早于EPO-018B的峰为聚合物的峰)；
A s-----对照溶液色谱图中主峰的峰面积。
保留时间为8.2min。
附图说明
1、图1为猕猴皮下注射100μg.kg -1剂量，血红蛋白(Hgb)和网织红细胞(Ret)时间变化
2.图2为猕猴皮下注射500μg.kg -1剂量，血红蛋白(Hgb)和网织红细胞(Ret)时间变化
3.图3为猕猴皮下注射1500μg.kg -1剂量，血红蛋白(Hgb)和网织红细胞(Ret)时间变化
4.图4为猕猴静脉注射100μg.kg -1剂量，血红蛋白(Hgb)和网织红细胞(Ret)时间变化
具体实施方式
本发明进一步通过如下实施例进行说明，所述实施例不理解为进一步的限定。本领域技术人员易于理解所述的特定方法和结果仅仅是说明性的。
实施例1
Figure PCTCN2018125599-appb-000003
称取处方量的磷酸二氢钠6.0g和磷酸氢二钠4.5g溶于800ml注射用水中，加入氯化钠4.0g，搅拌溶解；然后加入0.1％的活性炭至上述溶液并置60℃水浴中保温15min并趁热过滤脱炭，取续滤液冷却至20℃；称取处方量的培化西海马肽4.0g，缓慢搅拌使之溶解，并用磷酸二氢钠或氢氧化钠分别调节药液pH至3.0、4.0、5.0、6.0、7.0；采用注射用水将上述药液分别定容至1000ml，最后将药液用0.22μm的微孔滤膜过滤，分装至西林瓶中，充氮气后压塞，轧盖。将样品分别置25℃和40℃条件下考察其稳定性，考察指标为外观、有关物质和含量，结果见表1。
表1
Figure PCTCN2018125599-appb-000004
Figure PCTCN2018125599-appb-000005
实施例2
Figure PCTCN2018125599-appb-000006
称取处方量的磷酸二氢钠6.0g和磷酸氢二钠4.5g溶于800ml注射用水中，加入氯化钠，搅拌溶解；然后加入0.1％的活性炭至上述溶液并置60℃水浴中保温15min并趁热过滤脱炭，待空白辅料冷却后测pH(5.0～6.0)，若不在范围内加入适量盐酸或氢氧化钠溶液调节药液的pH至5.0～6.0，取续滤液冷却至20℃；称取处方量的培化西海马肽4.0g，缓慢搅拌使之溶解，采用注射用水将上述药液分别定容至1000ml，最后将药液用0.22μm的微孔滤膜过滤，分装至预灌封注射器中，充氮气后压塞。将样品分别置25℃和40℃条件下考察其稳定性，考察指标为外观、有关物质和含量，结果见表3。
表2
Figure PCTCN2018125599-appb-000007
Figure PCTCN2018125599-appb-000008
实施例3
Figure PCTCN2018125599-appb-000009
称取处方量的磷酸二氢钠和磷酸氢二钠溶于800ml注射用水中，加入氯化钠4.0g，搅拌溶解；然后加入0.1％的活性炭至上述溶液并置60℃水浴中保温15min并趁热过滤脱炭，取续滤液冷却至20℃；待空白辅料冷却后测pH(5.0～6.0)，若不在范围内加入适量盐酸或氢氧化钠溶液调节药液的pH至5.0～6.0，称取处方量的培化西海马肽适量，缓慢搅拌使之溶解，采用注射用水将上述药液分别定容至1000ml，最后将药液用0.22μm的微孔滤膜过滤，分装至预灌封注射器中，充氮气后压塞。将样品分别置25℃和40℃条件下考察其稳定性，考察指标为外观、有关物质和含量，结果见表3。
表3
时间(月) 温度(℃) 性状 聚合物杂质(％) 总杂(％) 含量(％)
0 25 无色澄明液体 0.24 1.02 99.6％
3 25 无色澄明液体 0.24 1.03 99.6％
6 25 无色澄明液体 0.25 1.08 99.5％
3 40 无色澄明液体 0.23 1.07 99.5％
6 40 无色澄明液体 0.28 1.13 99.5％
实施例4
Figure PCTCN2018125599-appb-000010
称取处方量的磷酸二氢钠和磷酸氢二钠溶于800ml注射用水中，加入氯化钠4.0g，搅拌溶解；然后加入0.1％的活性炭至上述溶液并置60℃水浴中保温15min并趁热过滤脱炭，取续滤液冷却至20℃；待空白辅料冷却后测pH(5.0～6.0)，若 不在范围内加入适量盐酸或氢氧化钠溶液调节药液的pH至5.0～6.0，称取处方量的培化西海马肽适量，缓慢搅拌使之溶解，采用注射用水将上述药液分别定容至1000ml，最后将药液用0.22μm的微孔滤膜过滤，分装至预灌封注射器中，充氮气后压塞。将样品分别置25℃和40℃条件下考察其稳定性，考察指标为外观、有关物质和含量，结果见表4。
表4
时间(月) 温度(℃) 性状 聚合物杂质(％) 总杂(％) 含量(％)
0 25 无色澄明液体 0.22 1.03 99.5％
3 25 无色澄明液体 0.23 1.05 99.5％
6 25 无色澄明液体 0.23 1.09 99.4％
3 40 无色澄明液体 0.24 1.11 99.4％
6 40 无色澄明液体 0.26 1.14 99.4％
实施例5
Figure PCTCN2018125599-appb-000011
称取处方量的磷酸二氢钠和磷酸氢二钠溶于800ml注射用水中，加入氯化钠4.0g，搅拌溶解；然后加入0.1％的活性炭至上述溶液并置60℃水浴中保温15min并趁热过滤脱炭，取续滤液冷却至20℃；待空白辅料冷却后测pH(5.0～6.0)，若不在范围内加入适量盐酸或氢氧化钠溶液调节药液的pH至5.0～6.0，称取处方量的培化西海马肽适量，缓慢搅拌使之溶解，采用注射用水将上述药液分别定容至1000ml，最后将药液用0.22μm的微孔滤膜过滤，分装至预灌封注射器中，充氮气后压塞。将样品分别置25℃和40℃条件下考察其稳定性，考察指标为外观、有关物质和含量，结果见表5。
表5
时间(月) 温度(℃) 性状 聚合物杂质(％) 总杂(％) 含量(％)
0 25 无色澄明液体 0.16 0.93 99.6％
3 25 无色澄明液体 0.17 0.94 99.6％
6 25 无色澄明液体 0.19 0.96 99.5％
3 40 无色澄明液体 0.19 0.97 99.5％
6 40 无色澄明液体 0.21 1.01 99.6％
试验例一 溶血试验
1、受试物：
1.1供试品：实施例3-5制备的培化西海马肽注射液；
1.2溶媒：氯化钠注射液。
2、实验方法：
2.1血球浮液的配制：取犬血5ml，用玻璃棒搅动血液，除去纤维蛋白原，使之成为脱纤血液。加入0.9％氯化钠溶液约10倍量，摇匀，1500转/分钟离心15分钟，除去上清液，沉淀的红细胞再用0.9％氯化钠溶液按上述方法洗涤3次，至上清液不显红色为止。量取血球1.0ml，加生理盐水稀释至50ml，配成2％的混悬液供试验用。
2.2药液配制：将实施例3实施例4注射液用生理盐水稀释至1.00mg/ml，混匀备用。
2.3加样
试验一和试验二分别取试管8支，按下列顺序加入各种溶液
Figure PCTCN2018125599-appb-000012
第1到第5管为受试物管，第6管为阴性对照管，第7管为阳性对照管，第8管为溶媒对照管。将各管溶液轻轻摇匀，置37℃水浴箱中，观察并记录15min、30min、45min、1h、2h、3h的结果。每观察时间点拍照。如溶液变清并染红色，即表示溶血。必要时可用显微镜观察红细胞是否破裂。
表6培化西海马肽注射液溶血实验观察表(试验一)
Figure PCTCN2018125599-appb-000013
表7培化西海马肽注射液溶血实验观察表(试验二)
Figure PCTCN2018125599-appb-000014
Figure PCTCN2018125599-appb-000015
表8培化西海马肽注射液溶血实验观察表(试验三)
Figure PCTCN2018125599-appb-000016
培化西海马肽注射液进行溶血试验，除阳性对照管外所有受试管均未发生显著溶血和凝血现象，表明培化西海马肽注射液未引起溶血和凝血现象。
试验例二、一般药理、局部刺激性研究
表9实施例3-5制备的培化西海马肽注射液药理研究总结
Figure PCTCN2018125599-appb-000017
试验二表明本发明制备的培化西海马肽注射液安全性，未对神经、心血管、呼吸系统和皮下组织产生过敏反应。
试验例三、猕猴单次皮下或静脉注射培化西海马肽后的药代及药效动力学研究
猕猴单次皮下注射实施例3制备的培化西海马肽(100，500和1500g.kg -1，低、中、高剂量)，各剂量组之间，末端相半衰期t 1/2随剂量增加而延长，全身清除率CL随剂量增加而逐渐减慢，提示在100～1500g.kg -1范围内，药物在猕猴体内呈非 线性药代动力学特征。
猕猴静脉注射100g.kg -1实施例3制备的培化西海马肽后2分钟血清抗原浓度达到最高10081.5±999.5ng.mL -1,随后逐渐消除，给药后72小时，血清抗原浓度降至本底水平。AUC(0-t)为19835±758.6(ng·h)mL -1，(P<0.001vs sc 100μg.kg -1),AUC(0-∞)为207020±758.6(ng·h)mL -1(P<0.001vs sc 100μg.kg -1),与等剂量sc组相比有显著性统计学意义差别。末端相半衰期t 1/2β为17.4±0.6h，与sc100μg.kg -1给药相比均有统计学意义差别(P<0.01)，全身清除率CL为5.0±0.2mL.h -1.kg -1。
表10猕猴皮下和静脉单次给药药代动力学数据
Figure PCTCN2018125599-appb-000018
药效动力学研究表明，培化西海马肽剂量依赖性地增加猕猴血红蛋白水平，皮下注射100和500g.kg -1剂量组在第14天的血红蛋白增长值分别为1.9和2.3g/dL，1500μg.kg -1组血红蛋白的最大值出现在第24天，增长幅度为3.4g/dL，至45天时还未降至给药前水平，呈现明显的长效效应；静脉注射100g.kg -1剂量组在第14天的血红蛋白(Hgb)增长值为3.2g/dL。与给药前相比，培化西海马肽剂量依赖性地刺激网织红细胞(Ret)的合成，皮下注射100和500g.kg -1剂量组在第6天的网织红细胞较给药前增加分别为527％和796％，1500μg.kg -1组网织红细胞最大值出现在第9天，较给药前增加1240％，3个剂量组至45天时均未降至给药前水平，呈现明显的长效效应；静脉注射100μg.kg -1剂量组在第6天的网织红细胞较给药前增加716％，见附图1～4。
猕猴连续4周皮下注射实施例5的培化西海马肽，第1周和第4周给药后达峰时间分别为20±6.9h和12.0±0.0h；达峰浓度Cmax分别为2408.8±262.3ng·mL-1和2346.1±247.6ng·mL-1，末端相半衰期T 1/2β分别为31.2±5.6h和30.1±3.8h。首 次和第4次注射后(注药间隔τ＝1W)的AUC (0-t)分别为100751±25759和126418±26571ng.h.mL-1，AUC (0-∞)分别为104974±26184和134961±29627ng.h.mL-1，蓄积因子(AUC第4周/AUC第1周)为1.27±0.09，提示连续皮下注射给药500μg·kg-1培化西海马肽后在体内没有明显蓄积。

Claims (17)

  1. 培化西海马肽药物组合物，其特征在于，包括活性成分培化西海马肽、缓冲液和等渗调节剂，所述培化西海马肽的结构为：
    Figure PCTCN2018125599-appb-100001
    n选自400-600，优选455。
  2. 根据权利要求1所述的培化西海马肽药物组合物，其特征在于，所述药物组合物的剂型为注射液，其中单位剂量中培化西海马肽的浓度为0.1mg/ml～100mg/ml，优选1mg/ml～20mg/ml，更优选2mg/ml、4mg/ml或6mg/ml。
  3. 根据权利要求2所述的培化西海马肽药物组合物，其特征在于，所述注射液中包含0.05％～5.0％(W/V)的培化西海马肽，优选0.1％～1.0％(W/V)。
  4. 根据权利要求2所述的培化西海马肽药物组合物，其特征在于，所述组合物中包含0.1％～5.0％(W/V)的缓冲盐，优选0.3％～3.0％(W/V)，更优选0.5％～1.5％。
  5. 根据权利要求2所述的培化西海马肽药物组合物，其特征在于，所述组合物中包含0.05％～5.0％(W/V)的等渗调节剂，优选0.1％～1.0％(W/V)。
  6. 根据权利要求4所述的培化西海马肽药物组合物，其特征在于，所述缓冲液选自磷酸盐缓冲液、醋酸盐缓冲液、枸橼酸盐缓冲液、碳酸盐缓冲液、酒石酸盐缓冲液、Tris缓冲液或组氨酸盐缓冲液，优选醋酸盐缓冲液或磷酸盐缓冲液，更优选磷酸二氢盐和磷酸氢二盐。
  7. 根据权利要求5所述的培化西海马肽药物组合物，其特征在于，所述等渗调节剂选自氯化钠、甘露醇、山梨醇、甘油、葡萄糖或木糖醇的一种或多种，优选甘露醇或氯化钠。
  8. 根据权利要求1～7任一项所述的培化西海马肽药物组合物，其特征在于，所述药物组合物的pH范围为4.0至7.0，优选5.0至6.0。
  9. 根据权利要求8所述的培化西海马肽药物组合物，其特征在于，所述缓冲盐选自磷酸二氢钠和磷酸氢二钠，重量比为1～10：1，优选1～3：1，更优选1.2～2：1。
  10. 根据权利要求9所述的培化西海马肽药物组合物，其特征在于，所述培化西海马肽注射液包含0.1％～2％(W/V)的培化西海马肽，0.1％～2.0％(W/V)的磷酸二氢钠，0.1％～2.0％(W/V)的磷酸氢二钠，0.1％～2.0％(W/V)的氯化钠；优选的，所述培化西海马肽注射液包含0.1％～1％(W/V)的培化西海马肽，0.2％～1％(W/V)的磷酸二氢钠，0.1％～0.6％(W/V)的磷酸氢二钠，0.1％～1.0％(W/V)的氯化钠。
  11. 根据权利要求1或10所述的培化西海马肽药物组合物，其特征在于，所述培化西海马肽与缓冲盐的重量比为1:1～10，优选1:2～4。
  12. 根据权利要求1或10所述的培化西海马肽药物组合物，其特征在于，所述培化西海马肽与等渗调节剂的重量比为1:0.5～10，优选1:1～2。
  13. 根据权利要求1或10所述的培化西海马肽药物组合物，其特征在于，所述培化西海马肽、缓冲盐与等渗调节剂的重量比为1:1～10：0.5～10，优选1:2～4:1～2，更优选1：2.8：1。
  14. 制备培化西海马肽药物组合物的方法，包括以下步骤：
    1)将缓冲盐和等渗调节剂溶于注射用水；
    2)加入活性炭，过滤脱炭得中间体药液；
    3)将培化西海马肽溶解至步骤2)的药液，搅拌溶解、过滤、分装。
  15. 根据权利要求1-13所述的培化西海马肽药物组合物在制备用于治疗以缺乏红细胞生成素或红细胞群缺少或缺陷疾病的应用，优选贫血。
  16. 一种治疗以缺乏红细胞生成素或红细胞群缺少或缺陷疾病的方法，给予患者0.02-0.10mg/kg的初始计量，此后每26-30天给予0.015-0.15mg/kg的维持剂量，以维持血红蛋白在10.0-12.0g/dL的范围内，优选地，给予患者0.025mg/kg、0.05mg/kg或0.08mg/kg的初始计量，此后每28天给予0.015-0.16mg/kg的维持剂量，以维持血红蛋白在10.0-12.0g/dL的范围内。
  17. 根据权利要求16所述的方法，所述缺乏红细胞生成素或红细胞群缺少或缺陷疾病为贫血，优选慢性肾功能衰竭所致的贫血症。
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