CN114533653A - 一种人促红素杂合Fc融合蛋白相变型制剂及其制备方法 - Google Patents
一种人促红素杂合Fc融合蛋白相变型制剂及其制备方法 Download PDFInfo
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Abstract
本发明属于生物技术领域，具体涉及一种人促红素杂合Fc融合蛋白相变型制剂及其制备方法。所述人促红素杂合Fc融合蛋白，是利用重组DNA技术、由CHO细胞表达的杂合Fc融合蛋白，其结构包括：人促红素和杂合型Fc片段。本发明所述人促红素杂合Fc融合蛋白制剂包含人促红素杂合Fc融合蛋白原液和原位凝胶基质，不含可能引起安全性风险的人血白蛋白和其他外源性有害物质，在保证制剂长期储存稳定性的同时，有效避免了临床用药的安全性风险。本发明所述制剂具有特殊的理化性能，在室温下为液态溶胶，便于工业化生产，经皮下注射给药后可转变成半固态凝胶，实现缓释作用。本发明提供了制备方法，制成的制剂质量稳定，临床用于治疗贫血。
Description
技术领域
本发明属于生物技术领域，具体涉及一种人促红素杂合Fc融合蛋白相变型制剂及其制备方法。
背景技术
天然人促红素是一种调节红细胞生成的多肽类激素，90％由肾脏产生。目前临床普遍使用的人促红素是一种短效型的基因工程化重组人促红素，每周需给药2～3次，临床广泛用于肾性贫血、肿瘤化疗引起的贫血以及其他贫血症的治疗。
本发明涉及的EPO-HyFc融合蛋白是由两条各含411个氨基酸的结构单元通过一对二硫键连接的同源二聚体，其中，人促红素部分的氨基酸序列与天然人促红素一致；HyFc则是由人IgD和人IgG4杂合而成。采用人促红素与HyFc融合，可延长产品半衰期、降低临床给药频次；采用人IgD和人IgG4杂合而成的HyFc具有一般Fc融合蛋白所不具有的两项优势，一是没有抗体依赖的细胞毒性效应和补体依赖的细胞毒性效应，更增强了产品的安全性；二是在铰链区有更好的柔性，使功能蛋白(人促红素)部分能更好地发挥作用，从而使药物分子能够更好地发挥有效性。
人促红素-HyFc融合蛋白原液用缓冲液稀释后即可制成水溶液型制剂，经注射途径给药，可实现每周给药1次，较短效型EPO的每周给药2～3次有明显临床优势。进一步，考虑到适用人群大多为消耗性疾病(肾衰、癌症)患者，体能状态已极为虚弱，用药依从性往往不佳；此外，此类患者往往因经历多次注射而导致血管壁受损严重，静脉给药途径有局限性。因此，将人促红素-HyFc融合蛋白原液与原位凝胶基质制成相变型制剂，经皮下注射给药后达到药物缓释的目的，实现每2～3周给药一次，可有效降低给药频次、减轻患者注射负担、改善患者反复注射的痛苦、提高用药依从性。
考虑到产品的商业化投产，所选辅料必须便于规模化放大，以达到商品化投产目的。因此，需要针对上述人促红素-HyFc融合蛋白原位凝胶开发一种适合商业化生产的制备工艺，以形成一种可以规模化投产的、质量稳定可控的人促红素-HyFc融合蛋白相变型制剂产品。
发明内容
本发明的目的是克服现有技术不足，提供一种人促红素杂合Fc融合蛋白(简称：EPO-HyFc融合蛋白)相变型制剂，临床用于治疗贫血。
本发明提供了人促红素-HyFc融合蛋白相变型制剂的制备方法。
本发明的目的可通过以下技术方案实现：
所述人促红素杂合Fc融合蛋白相变型制剂，包含活性成份人促红素杂合Fc融合蛋白(活性成分)原液和原位凝胶基质。
所述人促红素杂合Fc融合蛋白原液包含人促红素杂合Fc融合蛋白和稀释液，原位凝胶基质为泊洛沙姆407。
所述人促红素杂合Fc融合蛋白(简称：EPO-HyFc融合蛋白)是利用重组DNA技术、由CHO细胞表达的杂合Fc融合蛋白，其结构包括：人促红素和杂合型Fc片段，所述杂合型Fc片段由人Ig D和人IgG4杂合而成。所述人促红素杂合Fc融合蛋白序列如SEQ ID NO：1所示。
所述稀释液包含精氨酸(90mmol/L～110mmol/L)、氯化钠(95mmol/L～105mmol/L)、泊洛沙姆188(0.10％～0.20％)、枸橼酸-枸橼酸钠(10mmol/L～15mmol/L)。
所述人促红素杂合Fc融合蛋白相变型制剂中的活性成分人促红素杂合Fc融合蛋白浓度范围为0.01％～0.15％(w/w)，优选0.05％～0.10％(w/w)。
所述人促红素杂合Fc融合蛋白相变型制剂中的原位凝胶基质泊洛沙姆407的浓度范围为15％～25％(w/w)，优选20％～22％(w/w)。
本发明所选基质可通过市售渠道购得，货源充足稳定，可确保人促红素杂合Fc融合蛋白相变型制剂产品的商业化投产。
本发明的人促红素杂合Fc融合蛋白相变型制剂的制备方法如下：
称取原位凝胶基质，加适量注射用水搅拌溶解，加入适量稀释液混匀，～4℃冷藏过夜，得溶液I；将溶液I经微孔过滤，备用(溶液II)。将处方量的人促红素杂合Fc融合蛋白原液用溶液II稀释至总量，得半成品，经除菌过滤、灌装、加塞、轧盖、包装，即得成品。
有益效果：
本发明所述人促红素杂合Fc融合蛋白制剂包含人促红素杂合Fc融合蛋白原液和原位凝胶基质，不含可能引起安全性风险的人血白蛋白和其他外源性有害物质，在保证制剂长期储存稳定性的同时，有效避免了临床用药的安全性风险。本发明所述制剂具有特殊的理化性能，在室温下为液态溶胶，便于工业化生产，经皮下注射给药后可转变成半固态凝胶，实现缓释作用。本发明提供了制备方法，制成的制剂质量稳定，临床用于治疗贫血。
本发明制备方法得到的人促红素杂合Fc融合蛋白制剂外观呈无色或微黄色澄明溶胶状液体，经各项稳定性试验，结果表明，该制剂的质量稳定可控；在SD大鼠中进行的药代动力学试验结果显示，EPO-HyFc融合蛋白原位凝胶、EPO-HyFc融合蛋白水针、普通型EPO三组t1/2的比值为3.03：2.46：1，说明EPO-HyFc融合蛋白相变型制剂在体内的清除最慢，EPO-HyFc融合蛋白水针次之，普通型EPO最快。在SD大鼠中进行的药效学试验结果显示，EPO-HyFc融合蛋白相变型制剂每2周给药一次的疗效与EPO-HyFc融合蛋白水针每周给药1次、普通型EPO每周给药2次的疗效相当。
具体实施方式
实施例1
稀释液处方：
| 成份 | 稀释液1 | 稀释液2 | 稀释液3 |
| 精氨酸(mmol/L) | 90 | 100 | 110 |
| 泊洛沙姆188(％) | 0.10 | 0.15 | 0.20 |
| 氯化钠(mmol/L) | 95 | 100 | 105 |
| 枸橼酸-枸橼酸钠(mmol/L) | 10 | 10 | 15 |
| 注射用水制成 | 1L | 1L | 1L |
人促红素-HyFc融合蛋白注射剂处方(单位：g)。
注：此处稀释液配制时注射用水的量包含溶解泊洛沙姆407的注射用水。
制备方法：按上述处方，称取泊洛沙姆407，加注射用水搅拌溶解，加入稀释液混匀，～4℃冷藏过夜，得溶液I；将溶液I经微孔过滤，备用(溶液II)。将处方量的人促红素杂合Fc融合蛋白原液用溶液II稀释至总量，得半成品，经除菌过滤、灌装、加塞、轧盖、包装，即得成品，于2～8℃保存。
以上实施例中，处方6由于黏度较大，在制备过程中有明显搅拌阻力，考虑到蛋白质药物的固有特性，生产过程不宜采用剪切力过大的搅速，因此，预计处方6在生产放大的过程中会因搅速过大而影响产品质量。采用处方1～5制成的成品进行进一步试验。
实施例2
人促红素-HyFc融合蛋白原位凝胶的物理性能试验。
相转变温度测定采用试管倒置法，将成品从2～8℃的冰箱中取出，吸取5ml至试管中，将温度计插入溶胶。将试管置入水浴中(水浴液面高于溶胶内容物约2～3cm)，缓慢升温(升温速率控制在每分钟升高约1℃左右，测定范围15～60℃)。将试管倾斜，观察内容物由自由流动的溶胶状态转变成不能自由流动的凝胶状态时，记录转相变温度。
用黏度计检测黏度，用pH计检测pH值。
| 检查 | 处方1 | 处方2 | 处方3 | 处方4 | 处方5 |
| 相转变温度 | 无明显相转变 | 37.1℃ | 36.4℃ | 35.4℃ | 35.0℃ |
| 黏度(mPa·s) | NA | 47 | 53 | 57 | 59 |
| pH值 | 6.0 | 6.1 | 6.2 | 6.1 | 6.2 |
处方1在测定温度范围内无明显相转变，采用处方2～5制成的成品进行进一步试验。
三、实施例3
人促红素-HyFc融合蛋白原位凝胶的强制降解试验。
采用强制降解条件(40℃±2℃)，选择“纯度”作为关键质量指标(可接受限度：≥95.0％)，对各处方产品进行稳定性考察，结果如下。
由上表可知，处方2～5在所述强制降解条件下放置5天和10天，蛋白纯度均在合格范围内，产品质量稳定；处方3、4的蛋白纯度与0时相比变化不明显，可作为优选处方。
实施例4
人促红素-HyFc融合蛋白原位凝胶的长期稳定性研究(条件：2～8℃)。
由上表可知，本品在拟定的储存条件(2～8℃)下放置24个月，各项关键质量指标与0月相比无明显变化，证明拟定的处方工艺合理可行，可确保产品在长期储存时质量稳定。
实施例5
本发明临床用于治疗贫血。
人促红素-HyFc融合蛋白制剂的药效学研究(慢性肾衰模型)。
在慢性肾衰研究中，考察了EPO-HyFc融合蛋白水针每周1次静脉注射、EPO-HyFc融合蛋白原位凝胶每2周1次皮下注射后对5/6肾切除手术诱导的SD大鼠肾性贫血的改善作用。根据HGB和体重挑选成模大鼠随机分为：模型对照组、阳性对照组(市售EPO)、供试水针1.5～15μg/kg(iv)，供试凝胶1.5～15μg/kg(sc)，每组12只。假手术组10只。阳性对照组1每周给药2次，共6次；其余各给药组每周给药1次，共3次。结果显示，本实验条件下，供试水针每周1次或供试凝胶每2周1次注射，在1.5～15μg/kg的剂量范围内能呈剂量依赖性地改善5/6肾切除诱导的大鼠贫血症状。供试水针每周1次静脉给药和供试凝胶每2周1次皮下给药的效果接近，且供试品高剂量组每周1次给药(水针)或每2周1次(凝胶)给药的效果同500IU/kg的阳性对照品(市售EPO)每周给药2次的效果相当。
以上试验结果表明，本发明涉及的人促红素-HyFc融合蛋白水针及凝胶均可以达到改善贫血、延长给药间隔、降低给药频次的目的，凝胶制剂的给药间隔更长、给药频次更低。
实施例6
人促红素-HyFc融合蛋白制剂的药代动力学(PK)研究。
在SD大鼠中考察了供试品(人促红素-HyFc融合蛋白水针、凝胶)单次皮下注射给药的药代动力学特征，同时与对照品(市售EPO)比较。试验选用SD大鼠，随机分组，每组雌雄各4只，分为：供试品水针组(10μg/kg)、供试品凝胶组(10μg/kg)和市售EPO对照组(10μg/kg)。结果显示，相同摩尔剂量的供试品与市售对照品相比，EPO-HyFc融合蛋白原位凝胶、EPO-HyFc融合蛋白水针、普通型EPO三组t1/2的比值为3.03：2.46：1，说明EPO-HyFc融合蛋白原位凝胶制剂在体内的清除最慢，EPO-HyFc融合蛋白水针次之，普通型EPO最快。
以上试验结果表明，本发明涉及的人促红素-HyFc融合蛋白相变型凝胶制剂可以达到延长给药间隔、降低给药频次的目的。
序列表
<110> 上海凯茂生物医药有限公司
<120> 一种人促红素杂合Fc融合蛋白相变型制剂及其制备方法
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<170> SIPOSequenceListing 1.0
<210> 1
<211> 411
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Tyr Ala Trp Lys Arg Met Glu Val Gly Gln Gln Ala Val Glu Val Trp
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Gln Gly Leu Ala Leu Leu Ser Glu Ala Val Leu Arg Gly Gln Ala Leu
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Lys Ala Val Ser Gly Leu Arg Ser Leu Thr Thr Leu Leu Arg Ala Leu
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Gly Ala Gln Lys Glu Ala Ile Ser Pro Pro Asp Ala Ala Ser Ala Ala
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Pro Leu Arg Thr Ile Thr Ala Asp Thr Phe Arg Lys Leu Phe Arg Val
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Tyr Ser Asn Phe Leu Arg Gly Lys Leu Lys Leu Tyr Thr Gly Glu Ala
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Cys Arg Thr Gly Asp Arg Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys
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Lys Lys Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr
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Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro
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Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
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Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
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Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
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Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
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Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
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Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
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Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
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Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
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Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
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Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
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Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
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Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
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Claims (10)
1.一种人促红素杂合Fc融合蛋白相变型制剂，其特征在于包含活性成份人促红素杂合Fc融合蛋白原液和原位凝胶基质。所述人促红素杂合Fc融合蛋白原液包含人促红素杂合Fc融合蛋白和稀释液，所述原位凝胶基质为泊洛沙姆407。
2.根据权利要求1所述的人促红素杂合Fc融合蛋白相变型制剂，其特征在于所述的人促红素杂合Fc融合蛋白相变型制剂中人促红素杂合Fc融合蛋白的浓度范围为0.01％～0.15％(w/w)。
3.根据权利要求2所述的人促红素杂合Fc融合蛋白相变型制剂，其特征在于所述的人促红素杂合Fc融合蛋白相变型制剂中人促红素杂合Fc融合蛋白的浓度范围为0.05％～0.10％(w/w)。
4.根据权利要求1所述的人促红素杂合Fc融合蛋白相变型制剂，其特征在于所述的人促红素杂合Fc融合蛋白相变型制剂中原位凝胶基质泊洛沙姆407的浓度范围为15％～25％(w/w)。
5.根据权利要求4所述的人促红素杂合Fc融合蛋白相变型制剂，其特征在于所述的人促红素杂合Fc融合蛋白相变型制剂中原位凝胶基质泊洛沙姆407的浓度范围为20％～22％(w/w)。
6.根据权利要求1所述的人促红素杂合Fc融合蛋白相变型制剂，其特征在于所述人促红素杂合Fc融合蛋白是利用重组DNA技术、由CHO细胞表达的杂合Fc融合蛋白，其结构包括：人促红素和杂合型Fc片段。
7.根据权利要求6所述的人促红素杂合Fc融合蛋白相变型制剂，其特征在于所述的杂合型Fc片段由人Ig D和人IgG4杂合而成。
8.根据权利要求1所述的人促红素杂合Fc融合蛋白相变型制剂，其特征在于所述稀释液包含精氨酸、氯化钠、泊洛沙姆188和枸橼酸-枸橼酸钠。
9.根据权利要求8所述的人促红素杂合Fc融合蛋白相变型制剂，其特征在于所述的稀释剂中精氨酸的浓度为90mmol/L～110mmol/L，氯化钠的浓度为95mmol/L～105mmol/L，泊洛沙姆188的浓度为0.10％～0.20％，枸橼酸-枸橼酸钠的浓度为10mmol/L～15mmol/L。
10.权利要求1～8中任一项所述的人促红素杂合Fc融合蛋白相变型制剂的制备方法，其特征在于包含以下步骤：称取原位凝胶基质，加注射用水搅拌溶解，加入稀释液混匀，～4℃冷藏过夜，得溶液I；将溶液I经微孔过滤，备用溶液II；将处方量的人促红素杂合Fc融合蛋白原液用溶液II稀释至总量，得半成品，经除菌过滤、灌装、加塞、轧盖、包装，即得成品。
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