Preparation And Content Analysis Of New Formulated Silicone Oil Emulsion And Its Application In Animal Model

Simethicone, a compound of polydimethylsiloxane(PDMS, 90.5%~99.0%) and silicon dioxide(SiO2, 4.0%~7.0%), is a stable non-ionic surfactant and mainly acts on bubble surface exists in the chyme and mucus of digestive tract, reduces the surface tension of bubble, and accelerates the bubble broken to release gas. One part of the released gas can be absorbed by the intestinal wall, and another part of it can be excreted with the intestinal peristalsis. Simethicone has been used in clinical therapeutics for the treatment of abdominal distension, preparation before gastrointestinal examination, functional dyspepsia, etc. Simethicone can be prepared into many forms, such as soft capsules, suspensions, emulsions and so on. Since 2001, simethicone emulsion produced by Berlin-Chemie AG in Germany has been approved to import by Chinese health departments with the imported drug registration standards(JX20100262) being released, and now the emulsion is still sold in the drugs domestic market. However, the emulsion is low in pH value, large in acidity, which would cause a certain irritation on oral mucosa and poor compliance to the patient. Besides, the emulsion has demulsification phenomenon(instability) between different batches and even the same batch. To improve the stability of simethicone emulsion, reduce the irritation on oral mucosa, and make the imported simethicone emulsion localization as soon as possible, this article conducted a preliminary study on the formulation and preparation technique of simethicone emulsion, and obtained a new formulation of simethicone emulsion(specification 100mg/mL), which has good practical value and clinical application.According to the “registration declaration date requirments of chemicals” in Provision for Drug Registration(CFDA Order No. 28), a new formulation of simethicone emulsion was developed with its formulation, preparation technique, analytical methods, quality standards, stability, and pharmacodynamic effects on the animal models being studied. And the aim was to accumulate data for the application for registration of the new formulation of simethicone emulsion. The study includes the following sections:Research on formulation and preparation technique of simethicone emulsion. Character, stability, viscosity and content of the emulsion were taken as the investigation indexes, the formula of simethicone emulsion was screened and optimized by single-factor test and orthogonal test, respectively. And the optimal formulation of simethicone emulsion was composed of 10% of simethicone raw materia, 10.0g of polyoxyl stearate(40) ester, 3.0g of glyceryl monostearate, 70 mg of sorbic acid, 250 mg of carbomer, 20 mg of sodium cyclamate, 40 mg of sodium saccharin, 180 mg of banana flavor, and right amount of sodium hydroxide solution(adjusting pH to 5.0~6.0), then purified water was added to 100 mL. The preparation technique of simethicone emulsion was as follows: Firstly, prescription volume of the stearic acid polyoxyl(40) ester was added into 15 mL purified water at 70℃, stirred for dissolution. Then formulation volume of the glycerol monostearate was added and stirred for dissolution. Subsequently, formulation volume of simethicone was added with stirring, and emulsified about 60 min at 70℃ with the rotating speed of 600r/min to obtain the primary emulsion. Formulation volume of carbomer swelled initially in 20 m L purified water and appropriate amount of sodium hydroxide solution were added into the primary emulsion and mixed well. After that, formulation volume of sorbic acid, sodium cyclamate, sodium saccharin and banana flavor dissolved in appropriate amount of purified water were added, and the pH was adjusted to 5.0~6.0 with sodium hydroxide solution. Finally, added purified water to 100 mL, mixed well, packed in glass bottles, and stoppered to obtain the simethicone emulsion.Establishment of analytical methods of simethicone emulsion.(1) Content determination and method validation of the main ingredient(polydimethylsiloxane) of simethicone emulsion: proper amount of the solutions of reference substance and testing substance were injected into 0.5mm potassium bromide absorption cell resepectively, and determined with IR(resolution of 4 cm-1, scanning for 20 times, scanning range from 4000 to 400 cm-1) at the wavelength of about 1260 cm-1 to get the absorbance values, while dry carbon tetrachloride was taken for blank correction. Then the infrared spectrograms were recorded to calculate the content through external standard method(based on polydimethylsiloxane). The calibration curve showed good linear correlation in the range of 1.6080~2.4120 mg/m L. Besides, specificity, accuracy, precision, stability, the limit of detection, durability and content of three batches of samples all met the relevant requirements of simethicone emulsion imported drug registration standards. The method was simple, accurate, sensitive, specific, and is suitable for determination of polydimethylsiloxane in the new simethicone emulsion.(2) Content determination and method validation of the preservative(sorbic acid) of simethicone emulsion: The UV was used to determine the content of sorbic acid, and the result met the quality requirements. The absorption values showed a good linear relationship between the concentration of 2μg/mL ~ 6μg/m L. Besides, the specificity, accuracy, precision, minimum detection limit, and solution stability were all in line with the relevant requirements of simethicone emulsion imported drug registration standards.(3) Examination and method validation of anti-foaming ability: The "cylinder method" embodied in simethicone emulsion imported drug registration standards was used, and the anti-foaming ability of the new formulation of simethicone emulsion met the quality requirement. Besides, the repeatability, solution stability, specificity, and intermediate precision of the method were good, and all excipients had no interference to the determination method.Study on quality standard of simethicone emulsion. Referring to the requirements of quality standards of simethicone emulsion in USP37, the import standards of simethicone emulsion(JX20100262), ChP 2010, and “Technical guiding principle for the normalization process of the establishment of chemicals quality standards”, the quality standard of this product was formulated combined with the formulation characteristics of the new simethicone emulsion and the results of stability. Then three batches of the emulsion were tested, and the results met the quality standard, which showed that the standard could be used to control the quality of new simethicone emulsion.Study on stability of simethicone emulsion. Influence factor test, accelerated test and long-term test were conducted with three batches of simethicone emulsion, respectively. In influence factor test, we had carried out high temperature test(60℃) and strong light irradiation test(4500±500Lx), and it was found that the character, foaming rate, stability, contents of sorbic acid and polydimethylsiloxane of the emulsion all had no significant change after 30 days under the conditions of high temperature and strong light irradiation. Besides, simethicone emulsion packaged according to commercially available, had good stability, and the indexes of character, foaming rate, stability, contents of sorbic acid and polydimethylsiloxane and so on, all had no significant change under the conditions of six months of accelerated test and nine months of long-term test, and the long-term test is continuing.Pharmacodynamic investigation of simethicone emulsion on gastrointestinal flatulence model of the mice. Firstly, the influence of different doses of FOS and the different time after gavaging FOS on the flatulence model were studied respectively, and finally we chose 7.5 g/kg of FOS to create the gastrointestinal flatulence model. Then the simethicone emulsion dissolved in appropriate amount water was given to investigate its efficacy. The results showed that simethicone emulsion had obvious defoaming effect to the mice, and the best time of defoaming effect was 2 h after gavaging the emulsion in the test.