Jones D S, Brown A F, Woolfson A D
School of Pharmacy, The Queen's University of Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland, United Kingdom.
J Pharm Sci. 2001 Dec;90(12):1978-90. doi: 10.1002/jps.1149.
This study examined the creep behavior and oscillatory and flow properties of tetracycline-containing, bioadhesive semisolid formulations, designed for localized treatment of periodontal disease. Formulations were prepared containing hydroxyethylcellulose (HEC, 1, 3, or 5% w/w), poly(vinylpyrrolidone) (PVP, 2 or 3% w/w), polycarbophil (PC, 1 or 3% w/w), and tetracycline (5% w/w, as the hydrochloride). In creep analysis, each formulation exhibited several distinct regions that were mathematically modelled using a multi-element Voigt model with a residual spring and dashpot. Increasing the concentrations of each polymeric component decreased the elastic compliance (J(0)) yet increased the residual viscosity. In oscillatory analysis, increased polymer concentrations increased the storage modulus (G'), the loss modulus (G") and the dynamic viscosity (eta'), yet decreased the loss tangent (tan delta). The relationships between G' or G" and frequency were observed to plateau at higher frequencies, which is indicative of polymer chain entanglement and network formation. With the exception of formulations containing 1% HEC, the formulations were elastic (tan delta < 1), with large G' and small J(0) values. All formulations exhibited pseudoplastic flow with thixotropy. Increasing concentrations of each polymeric component increased the zero-shear viscosity (determined using the Cross model) and was further evidence of polymer chain entanglement. Formulations containing 1% w/w HEC possessed excellent flow properties, however, their thixotropic behavior and essentially elastoviscous nature (large J(0) and tan delta) would be disadvantageous for use in the treatment of periodontal disease because of rapid removal from the pocket and relatively uncontrolled drug release. Despite their advantageous viscoelastic properties, the flow properties of formulations containing 5% w/w HEC were inappropriate, rendering administration through a periodontal syringe potentially difficult. Based on their rheological behavior, formulations containing HEC (3% w/w), PVP (2 or 3% w/w), and PC (1 or 3% w/w) would be suitable for clinical application. However, consideration of other physicochemical properties (e.g., bioadhesion, drug release kinetics) must be performed prior to selection of the most suitable formulation for clinical examination. This study has highlighted the successful complimentary application of creep analysis and oscillatory and flow rheometry for the characterization and development of bioadhesive semisolid formulations for the treatment of periodontal disease.
本研究考察了用于局部治疗牙周疾病的含四环素生物黏附性半固体制剂的蠕变行为、振荡特性和流动性质。制备了含有羟乙基纤维素（HEC，1%、3%或5% w/w）、聚维酮（PVP，2%或3% w/w）、聚卡波非（PC，1%或3% w/w）和四环素（5% w/w，盐酸盐形式）的制剂。在蠕变分析中，每种制剂均表现出几个不同的区域，使用带有残余弹簧和阻尼器的多元件沃伊特模型进行数学建模。增加每种聚合物组分的浓度会降低弹性顺应性（J(0)），但会增加残余粘度。在振荡分析中，聚合物浓度增加会使储能模量（G'）、损耗模量（G"）和动态粘度（η'）增加，但会降低损耗角正切（tan δ）。观察到G'或G"与频率之间的关系在较高频率时趋于平稳，这表明聚合物链缠结和网络形成。除了含有1% HEC的制剂外，其他制剂均具有弹性（tan δ < 1），G'值大而J(0)值小。所有制剂均表现出具有触变性的假塑性流动。增加每种聚合物组分的浓度会增加零剪切粘度（使用Cross模型测定），这进一步证明了聚合物链缠结。含有1% w/w HEC的制剂具有优异的流动性质，然而，它们的触变行为和基本的弹粘性性质（J(0)和tan δ大）对于牙周疾病治疗是不利的，因为会从牙周袋中快速清除且药物释放相对不受控制。尽管含有5% w/w HEC的制剂具有有利的粘弹性性质，但其流动性质不合适，使得通过牙周注射器给药可能困难。基于其流变行为，含有3% w/w HEC、2%或3% w/w PVP以及1%或3% w/w PC的制剂适合临床应用。然而，在选择最适合临床检查的制剂之前，必须考虑其他物理化学性质（如生物黏附性、药物释放动力学）。本研究突出了蠕变分析以及振荡和流动流变学在表征和开发用于治疗牙周疾病的生物黏附性半固体制剂方面的成功互补应用。
