Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA; Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
Int J Pharm. 2024 Mar 25;653:123794. doi: 10.1016/j.ijpharm.2024.123794. Epub 2024 Jan 10.
For proportionally formulated intermediate strengths of a topical product, the relationship of drug release across multiple strengths of a given product is not always well understood. The current study aims to assess the proportionality of tretinoin release rates across multiple strengths of tretinoin topical gels when manufactured using two different methods to understand the impact of formulation design on drug product microstructure and tretinoin release rate. Two groups of tretinoin gels of 0.04 %, 0.06 %, 0.08 % and 0.1 % strengths were manufactured. Gels in Group I were prepared by incorporating 4-10 % g/g of 1 % w/w tretinoin-loaded microparticles into a gel base. Gels in Group II were manufactured using 10 % g/g of the microparticles that were loaded with increasing amounts (0.4-1 % w/w) of tretinoin. The two groups of gels were characterized by evaluating microstructure using a polarized microscope, rheology using an oscillatory rheometer, and drug release using Vison® Microette™ Hanson vertical diffusion cells. The microscopic images were used to discriminate between the two groups of gels based on the abundance of microparticles in the gel matrix observed in the images. This abundance increased across gels of Group I and was similar across gels of Group II. The rheology parameters, namely viscosity at a shear rate of 10 s, shear thinning rate, storage, and loss modulus, increased across gels of Group I, and were not significantly different across gels of Group II. The release rate of tretinoin from the drug products was proportional to the nominal strength of the drug product in both Group I and Group II, with a correlation coefficient of 0.95 in each case, although the absolute release rates differed. Overall, changing the formulation design of tretinoin topical gels containing porous microparticles may change the physicochemical and structural properties, as well as the drug release rate of the product. Further, keeping the formulation design consistent across all strengths of microparticle-based topical gels is important to achieve proportional release rates across multiple strengths of a given drug product.
对于比例配方的局部产品中间强度，对于给定产品的多种强度，药物释放的关系并不总是很好理解。本研究旨在评估两种不同方法制造的 0.04%、0.06%、0.08%和 0.1%浓度的维 A 酸局部凝胶的维 A 酸释放率的比例性，以了解配方设计对药物产品的微观结构和维 A 酸释放率的影响。制备了两组 0.04%、0.06%、0.08%和 0.1%浓度的维 A 酸凝胶。第 I 组凝胶是通过将 4-10%g/g的 1%w/w载有维 A 酸的微粒子加入凝胶基质中制备的。第 II 组凝胶是使用载有不同量（0.4-1%w/w）维 A 酸的 10%g/g微粒子制造的。通过使用偏光显微镜评估微观结构、使用振荡流变仪评估流变学特性以及使用 Vison®Microette™Hanson 垂直扩散池评估药物释放来表征两组凝胶。使用显微镜图像来区分两组凝胶，根据图像中观察到的凝胶基质中微粒子的丰度进行区分。这种丰度在第 I 组凝胶中增加，并且在第 II 组凝胶中相似。流变学参数，即 10s 剪切速率下的粘度、剪切稀化率、储存和损耗模量，在第 I 组凝胶中增加，并且在第 II 组凝胶中没有显著差异。在第 I 组和第 II 组中，药物产品的维 A 酸释放率与药物产品的名义强度成正比，在每种情况下相关系数均为 0.95，尽管绝对释放率有所不同。总体而言，改变含有多孔微粒子的维 A 酸局部凝胶的配方设计可能会改变产品的物理化学和结构特性以及药物释放率。此外，保持基于微粒子的局部凝胶的所有强度的配方设计一致对于实现给定药物产品的多个强度的比例释放率很重要。
