Sadhale Y, Shah J C
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Int J Pharm. 1999 Nov 25;191(1):65-74. doi: 10.1016/s0378-5173(99)00287-2.
Glyceryl monooleate (GMO)-water cubic phase gel was previously shown to protect insulin from agitation induced aggregation. However, it is not known if insulin is biologically active in the gel and what effect agitation has on insulin in the gel. Therefore, the objective was to determine the stability of insulin in cubic phase gel in terms of its biological activity in a suitable animal model such as Sprague-Dawley rats. Effect of agitation on biological activity of insulin in cubic phase GMO gel was determined by subcutaneous injections of the agitated and non-agitated gels to two groups of previously fasted rats and measuring the effect on their blood glucose levels. Two groups of rats administered with agitated insulin solution and normal saline were used as controls. The biological activity of insulin was evaluated by comparing AAC (area above the blood glucose level-time curve, in %-h), C(max) (maximum % decrease in blood glucose levels) and t(max) (time required to attain C(max), in h) values for the four groups of rats. Since cubic phase gel is highly viscous, therapeutic equivalency of insulin in the lamellar phase gel, which converts in situ into cubic phase gel, was compared to insulin solution with normal saline as the control, using AAC, C(max) and t(max) of the blood glucose profile. Insulin was biologically active in both agitated and non-agitated gels; however, upon agitation, insulin in solution totally lost its hypoglycemic activity. Agitation of insulin in the cubic phase gel was seen to have very little deleterious effect on its biological activity. Insulin in the lamellar phase gel was not only biologically active but also therapeutically equivalent to insulin solution based on AAC (327.9+/-100.8 and 431.7+/-113.3), C(max) (57. 1+/-7.0 and 70.2+/-6.5) and t(max) (2.8+/-0.7 and 4.0+/-1.7) for the lamellar phase gel and insulin solution, respectively (no significant difference, P0.05). In summary, GMO cubic phase gel protected insulin from agitation induced aggregation, and insulin was biologically active in the gel.
单油酸甘油酯（GMO）-水立方相凝胶先前已被证明可保护胰岛素免受搅拌诱导的聚集。然而，尚不清楚胰岛素在该凝胶中是否具有生物活性，以及搅拌对凝胶中的胰岛素有何影响。因此，目的是在合适的动物模型（如Sprague-Dawley大鼠）中，根据胰岛素的生物活性来确定其在立方相凝胶中的稳定性。通过将搅拌和未搅拌的凝胶皮下注射到两组预先禁食的大鼠中，并测量对其血糖水平的影响，来确定搅拌对立方相GMO凝胶中胰岛素生物活性的影响。两组分别给予搅拌胰岛素溶液和生理盐水的大鼠用作对照。通过比较四组大鼠的AAC（血糖水平-时间曲线下面积，以%-h计）、C(max)（血糖水平最大降幅百分比）和t(max)（达到C(max)所需时间，以h计）值来评估胰岛素的生物活性。由于立方相凝胶具有高粘性，将原位转化为立方相凝胶的层状相凝胶中胰岛素的治疗等效性与以生理盐水为对照的胰岛素溶液进行比较，使用血糖曲线的AAC、C(max)和t(max)。胰岛素在搅拌和未搅拌的凝胶中均具有生物活性；然而，搅拌后，溶液中的胰岛素完全失去其降血糖活性。可见搅拌立方相凝胶中的胰岛素对其生物活性几乎没有有害影响。基于层状相凝胶和胰岛素溶液的AAC（分别为327.9±100.8和431.7±113.3）、C(max)（分别为57.1±7.0和70.2±6.5）和t(max)（分别为2.8±0.7和4.0±1.7），层状相凝胶中的胰岛素不仅具有生物活性，而且在治疗上等同于胰岛素溶液（无显著差异，P>0.05）。总之，GMO立方相凝胶保护胰岛素免受搅拌诱导的聚集，且胰岛素在该凝胶中具有生物活性。
