A recombinant human enzyme for enhanced interstitial transport of therapeutics
A recombinant human enzyme for enhanced interstitial transport of therapeutics
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DOI：
10.1016/j.jconrel.2006.05.027
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发表时间：
2006-08-28
影响因子：
10.8
通讯作者：
Frost, G. I.
中科院分区：
文献类型：
--
作者：
Bookbinder, L. H.;Hofer, A.;Frost, G. I.
皮下注射的治疗剂必须穿过皮肤的间质基质以到达其预期的靶点。这种复杂的三维结构限制了可以通过局部注射施用的药物的类型和数量。在这里，我们发现，在动物模型中，用高度纯化的重组人透明质酸酶（rHuPH 20）解聚间质基质的粘弹性成分，增加了局部注射药物的分散，在广泛的分子量范围内，而不会使组织变形。rHuPH 20增加了输注速率以及局部注射药物在全身血液中出现的模式和程度。特别是，rHuPH 20改变了药代动力学特征，并显着增加了局部注射的大蛋白治疗剂的绝对生物利用度。重要的是，在注射后24小时内，间质粘弹性屏障恢复，无组织学改变或炎症体征。rHuPH 20可以作为间质递送增强剂，其能够增加共注射药物的分散和生物利用度，这可以使得能够皮下施用治疗剂并代替静脉内递送。(c)2006 Elsevier B.V.保留所有权利。
Subcutaneously injected therapeutics must pass through the interstitial matrix of the skin in order to reach their intended targets. This complex, three-dimensional structure limits the type and quantity of drugs that can be administered by local injection. Here we found that depolymerization of the viscoelastic component of the interstitial matrix in animal models with a highly purified recombinant human hyaluronidase enzyme (rHuPH20) increased the dispersion of locally injected drugs, across a broad range of molecular weights without tissue distortion. rHuPH20 increased infusion rates and the pattern and extent of appearance of locally injected drugs in systemic blood. In particular, rHuPH20 changed the pharmacokinetic profiles and significantly augmented the absolute bioavailability of locally injected large protein therapeutics. Importantly, within 24 h of injection, the interstitial viscoelastic barriers were restored without histologic alterations or signs of inflammation. rHuPH20 may function as an interstitial delivery enhancing agent capable of increasing the dispersion and bioavailability of coinjected drugs that may enable subcutaneous administration of therapeutics and replace intravenous delivery. (c) 2006 Elsevier B.V. All rights reserved.