Goodwin Daniel J, Sepassi Shadi, King Stephen M, Holland Simon J, Martini Luigi G, Lawrence M Jayne
Institute of Pharmaceutical Science, King's College London , Stamford Street, London SE1 9NH, United Kingdom.
Mol Pharm. 2013 Nov 4;10(11):4146-58. doi: 10.1021/mp400138e. Epub 2013 Oct 22.
Production of polymer and/or surfactant-coated crystalline nanoparticles of water-insoluble drugs (nanosuspensions) using wet bead milling is an important formulation approach to improve the bioavailability of said compounds. Despite the fact that there are a number of nanosuspensions on the market, there is still a deficiency in the characterization of these nanoparticles where further understanding may lead to the rational selection of polymer/surfactant. To this end small-angle neutron scattering (SANS) measurements were performed on drug nanoparticles milled in the presence of a range of polymers of varying molecular weight. Isotopic substitution of the aqueous solvent to match the scattering length density of the drug nanoparticles (i.e., the technique of contrast matching) meant that neutron scattering resulted only from the adsorbed polymer layer. The layer thickness and amount of hydroxypropylcellulose adsorbed on nabumetone nanoparticles derived from fitting the SANS data to both model-independent and model dependent volume fraction profiles were insensitive to polymer molecular weight over the range Mv = 47-112 kg/mol, indicating that the adsorbed layer is relatively flat but with tails extending up to approximately 23 nm. The constancy of the absorbed amount is in agreement with the adsorption isotherm determined by measuring polymer depletion from solution in the presence of the nanoparticles. Insensitivity to polymer molecular weight was similarly determined using SANS measurements of nabumetone or halofantrine nanoparticles stabilized with hydroxypropylmethylcellulose or poly(vinylpyrrolidone). Additionally SANS studies revealed the amount adsorbed, and the thickness of the polymer layer was dependent on both the nature of the polymer and drug particle surface. The insensitivity of the adsorbed polymer layer to polymer molecular weight has important implications for the production of nanoparticles, suggesting that lower molecular weight polymers should be used when preparing nanoparticles by wet bead milling since nanoparticle formation is more rapid but with no likely consequence on the resultant physical stability of the nanoparticles.
使用湿珠磨法制备水不溶性药物的聚合物和/或表面活性剂包覆的结晶纳米颗粒（纳米混悬液）是提高所述化合物生物利用度的重要制剂方法。尽管市场上有许多纳米混悬液，但这些纳米颗粒的表征仍存在不足，进一步了解可能有助于合理选择聚合物/表面活性剂。为此，对在一系列不同分子量聚合物存在下研磨的药物纳米颗粒进行了小角中子散射（SANS）测量。对水性溶剂进行同位素取代以匹配药物纳米颗粒的散射长度密度（即对比匹配技术）意味着中子散射仅来自吸附的聚合物层。通过将SANS数据拟合到与模型无关和与模型相关的体积分数分布图来确定吸附在萘丁美酮纳米颗粒上的羟丙基纤维素的层厚度和量，在Mv = 47-112 kg/mol范围内对聚合物分子量不敏感，表明吸附层相对平坦，但尾部延伸至约23 nm。吸附量的恒定性与通过测量纳米颗粒存在下溶液中聚合物消耗确定的吸附等温线一致。使用用羟丙基甲基纤维素或聚（乙烯基吡咯烷酮）稳定的萘丁美酮或卤泛群纳米颗粒的SANS测量同样确定了对聚合物分子量的不敏感性。此外，SANS研究表明吸附量和聚合物层的厚度取决于聚合物和药物颗粒表面的性质。吸附的聚合物层对聚合物分子量的不敏感性对纳米颗粒的生产具有重要意义，表明在通过湿珠磨法制备纳米颗粒时应使用较低分子量的聚合物，因为纳米颗粒形成更快，但对所得纳米颗粒的物理稳定性可能没有影响。
