Introduction: Altrenogest (ALT) is widely used to regulate the estrous cycle of sows and mares; however, currently used oral solutions of ALT are deficient in terms of dose accuracy and stability during use. To resolve these problems, we aimed to prepare softgel capsules of ALT with a unit dose equal to the clinically administered dose.Method: The shell of the softgel capsule was mainly composed of gelatin and glycerol, with titanium dioxide and red iron oxide as masking agents. Using the shake flask method, the contents were screened for ethyl acetate as a lipophilic solubilizing carrier based on soya bean oil. The contents were automatically filled and compressed into softgel capsules by a softgel capsule machine. The quality of the prepared softgel capsules was evaluated through a drug content test, an in vitro release test, and stability studies. Furthermore, bioequivalence studies were conducted with atrenogest oral solution.Results: The content is an ALT concentration of 2% oil solution and the specification of the softgel is 20 mg/capsule. In in vitro dissolution experiments, the softgel capsules were rapidly disintegrated and released in three different pH buffers, with a cumulative release rate of nearly 100% at 1 h. The softgel capsules were stable at high temperature and under strong light for 10 days, and the concentration of ALT was >99% in the 6-month accelerated and long-term tests. In the bioequivalence study, Tmax of the softgel capsules was 2.20 ± 0.77 h, t1/2 was 6.36 ± 1.74 h, and Cmax was 64.65 ± 20.69 ng/ml. The main pharmacokinetic parameters Tmax, Cmax, AUC0−t, and AUC0−∞, did not differ significantly between the softgel capsules and the commercially available ALT oral solution (P > 0.05), and bioequivalence was demonstrated within the 90% confidence interval.Conclusion: The prepared softgel capsules have the advantages of higher content, ease of use with accurate dosing, good stability, and equivalence to ALT oral solution, implying that our softgels are ready for clinical use.
Huilin Song,Xingchen Wang,Siyu Hou,Yuqi Zhang,Xi Luo,Tengfei Li,Shunli Ji
Calcitriol is an active product of vitamin D produced by the liver and kidney hydroxylase metabolism with strong physiological activity. It is the preferred form of medicine for patients with insufficient bone mineralization due to chronic kidney disease. Calcitriol soft capsule is one of the common preparation forms, the main drug content of which is very low (1.55 μg g −1 ), and the pharmaceutical excipients interfere greatly, especially the oily matrix medium-chain triglycerides. Therefore, removing the interference of oily matrix is the main challenge in the content determination. At present, the commonly used sample purification method for the determination of calcitriol in soft capsules is liquid-liquid extraction, but it usually consumes a lot of toxic organic solvents and it is costly. The adoption of SPE purification method, on the one hand, requires specific experimental equipment, and on the other hand, the organic solvent used in the experiment may cause the dissolution of SPE column tube materials, which will interfere with the subsequent detection. Herein, in order to achieve a cost-effective and reliable determination of calcitriol soft capsule content, we developed a dispersive solid-phase (DSPE) extraction method that directly uses irregular silica as sorbent , which is followed by high-performance liquid chromatography equipped with a UV detector(HPLC-UV)analysis. Selective retention of calcitriol is achieved by the polar interaction between calcitriol and silica, what’s more, sufficient contact between washing solvent and sorbent can be guaranteed. Therefore, after pretreatment with DSPE, the interference of oily matrix on detection can be mostly removed and then improve the accuracy of the method compared to the SPE method. Under the optimal conditions of DSPE, calcitriol showed a good linear relationship in the range of 0.15−2.99 μg g −1 , the R 2 was 0.997. Satisfactory recoveries ranging from 101.1%–102.0% for calcitriol were achieved in the oily matrix at the levels of 0.75, 1.50 and 2.24 μg g −1 . And the intra-day and inter-day RSD were less than 2.5 % and 3.2 %. Meanwhile, the LOD and LOQ of calcitriol was 0.01 μg g −1 and 0.02 μg g −1 , which is in full compliance with the regulatory level fixed by the EU, China or other countries. This method was further verified to determine the content of calcitriol in commercial calcitriol soft capsules and the recoveries of three batches of products was 86.2 %–94.4 %. Based on these characteristics, the proposed method makes it possible to determine the low content of weakly polar drugs in the oily matrix in a simple, low-cost and reliable way.
危险品化学品经营许可证（带存储）