| Adapalene is the third generation of vitamin A acid drug of artificial synthesis. For external use, its preparation is 0.01%Adapalene Gel (DIFFERIN), which has satisfactory effect of anti-inflammation and improving the ability of keratinocyte. The clinic shows that it has good curative effect on acne, and better skin tolerability and less toxic and side effect than other vitamin A acids. The base of Adapalene Gel has good skin tolerability, and it can prevent the formation of acnes, In the local application of Adapalene, little penetrates the skin and little is absorbed. It has satisfactory curative effect and weak side effect on the light and medium acnes. This paper researches the material quality control method for Adapalene materials, designs and optimizes the formula of its gel preparation, and researches the preparation process and quality control method of Adapalene preparation.1. Study on quality control method for Adapalene raw material drugThis paper researches various indexes of raw material drug according to the pharmacopeia and technical guidelines for chemical drugs research. Adopt the non-aqueous titration method to research the method for content determination; adopt the high performance liquid chromatography (HPLC) to further research the intermediate and decomposition products of Adapalene. According to the synthesis method of Adapalene, determine four kinds of possible intermediate impurities, and make use of HPLC to realize the separation of Adapalene from four kinds of intermediate with different polarity. And make use of the same chromatogram conditions to separate from the decomposition products of this compound due to acid-base disturbance. Adopt HPLC to establish the quality control method for the matters in Adapalene raw materials.2. Study on preparation process of Adapalene According to the physical and chemical properties of Adapalene and the research situation of similar foreign products, combining with the physical and chemical properties of drugs and the actual application of gel base materials in China, design the gel formula of this product. Combining with the domestic requirements on popular auxiliary materials and gels, research the compatibility of Adapalene and auxiliary materials. In the similar foreign products, the content of methyl p-hydroxybenzoate and phenoxyethanol is 0.1%and 0.25% (w/w) respectively; EDTA is the anti-metallic-ion oxidant, and its dosage is usually 0.05～0.1%(05%in this formula); Poloxamer is the non-ion surface active agent, and its dosage is usually 0.1%, based upon which this paper optimizes the dosage of propylene glycol and Carbomer in the formula. This product is the white or white-like semisolid gel preparation, with moderate viscosity. It spreads well on the skin surface, with satisfactory moistening property and acceptable stability.The result indicates that the gel is stable at the conditions of high temperature, high humidity and strong sunshine.3. Study on quality control method for Adapalene preparationEstablish the quality control method for Adapalene gel. Adopt the HPLC gradient elution to determine the content of phenoxyethanol, methyl p-hydroxybenzoate and Adapalene in Adapalene Gel. The method was performed on a Tigerkin C18 column (4.6x 150mm,5μm). The mobile phase was the gradient elution with 0.02mo1·L-1 ammonium acetate buffer(pH3.0)-tetrahydrofuran-acetonitrile, moble phase A:tetrahydrofuran-acetonitrile: (17:83); moble phase B:0.02mol·L-1 ammonium acetate buffer(pH3.0).and the detection wavelength was set at 270nm. Flow rate:1.0 mL·min-1. The step of the gradient elution: 0～8min,80%B～72%B; 8～12min,72%B～5%B; 12～25min,5%B; 25～30min, 5%B～80%B。The linear scope is:Adapalene:4～40μg·mL-1(r=0.9999), phenoxyethanol: 4-40μg·mL-1(r=0.9999), p-hydroxybenzoate:10～100μg·mL-1(r=0.9999) The rate of recovery is 100.9%(RSD=1.1%),98.7%(RSD=1.4%) and 99.1%(RSD=1.3%) respectively. The determination result is that Adapalene:0.10%, phenoxyethanol:0.25%and methyl p-hydroxybenzoate:0.10%. |
PDF Full Text Request