Preparation And Content Analysis Of Xanthium Silicone Oil Suspension And Its Effect On Animal Model

Simethicone, a compound of polydimethylsiloxane(PDMS) and silicon dioxide(SiO2), is a white or off-white viscous oil-like liquid without special odour and taste,and can easily be dissolved in chloroform, hexane or toluene, but it is insoluble in water and ethanol. Besides, simethicone is also 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. So simethicone has good defoaming effect and the effect belongs to pure physical process. Due to its good bioavailability,simethicone has been widely used in abdominal distension which caused by gas accumulated in abdomen, abdominal discomfort, indigestion, postoperative abdominal distension and imageological examination, etc. So far, the simethicone preparations listed in foreign countries are mainly tablets, oral emulsions, suspensions, soft capsules,and there is only imported simethicone emulsion manufactured by the Berlin-Chemie AG in China. Simethicone dry suspension developed by our group, which belongs to class two according to the new "registration and classification of chemicals" method(SFDA), could be consulted neither on research paper nor the list of market and the only searchable result is the patent “simethicone dry suspension and its preparation method(publication No. CN 10505326 A)” applied by our research group.Simethicone being prepared into dry suspension, is not only simple in preparation technique and low in cost, but also has the characteristics of both solid preparation and liquid preparation, such as portable to carry and transport, stable in quality which is conducive to resolving the stability problems of suspensions during storage, and convenient to take for the elderly, children and patients with dysphagia and so on.Therefore, the development of simethicone dry suspension has important research significance and practical value.Combined with the supply and ratification situation of Chinese pharmaceutical excipient, our research group developed simethicone dry suspension(specification1000 mg: 40mg) with low cost and reasonable prescription process. And in order to control the quality of dry suspension effectively, we developed and validated an IR method for determination of simethicone dry suspension according to the analytical methods of relevant literature. Besides, to accumulate data for the preclinical study andapplication for registration of simethicone dry suspension, we had studied the stability of the dry suspension and its pharmacodynamic effects on the animal models.The study in the first part aimed to screen and optimize the formula and preparation technique of simethicone dry suspension. Taking the taste, solubility and suspensibility as investigation indexes, the formula of simethicone dry suspension was screened and optimized by single-factor test and orthogonal test, respectively. And the best prescription was that every 1000 mg of dry suspension contained simethicone 40 mg, sodium carboxymethyl cellulose 25 mg, xanthan gum 15 mg, Tween(80) 36 mg,Span(80) 4mg, croscarmellose sodium 10 mg, sucrose 870 mg, and proper amount of banana essence and 75% ethanol solution. Among them, simethicone was the raw materials; CMC-Na and xanthan gum were taken as the suspending agent; Tween 80 and Span 80 were combined as the wetting agent; cross-linked CMC-Na was the disintegrant agent; sucrose was adsorption filling agent; banana flavor and 75%ethanol solution were respectively the flavoring and wetting agent. Meanwhile, the optimal preparation technique was as follows: simethicone raw material and the wetting agent(Tween 80 and Span 80) were mixed and grinded for about 30 min, and part of sucrose was added to adsorb the mixture. After that, the residual excipients were added, stirred up and mixed through sieving according to the equivalent addition method. Then made soft material with appropriate amount of 75% ethanol, sieved for wet granules, dried at 40-60℃ for 3 h, sprayed banana essence, granulated with 20 mesh sieve, and finally packaged to obtain the simethicone dry suspension with each bag of 1g.The second part was to establish the analysis methods of content and defoaming capability of simethicone dry suspension, which were all the important indicators for the quality control of the dry suspension. With reference to the foreign content determination method of other simethicone preparations and the examination method of "anti-foaming ability" in the simethicone emulsion import standards, we had obtained and validated the methods, which were respectively applicable to the content determination and defoaming capability examination of simethicone dry suspension.In the third part, the examination items of simethicone dry suspension, such as character, content, defoaming capacity, sedimentation ratio, loss on drying and so on,were studied mainly based on the relevant contents and requirements of ChP 2010,USP36 and the import standards of simethicone emulsion. Then we formulated the quality standards of simethicone dry suspension, and tested three batches ofsimethicone dry samples. The results met the quality standards, which indicated that the standards could be used to control the quality of simethicone dry suspension.Part four was about study on the stability of simethicone dry suspension, and influence factor test, accelerated test and long-term test were conducted with three batches of simethicone dry suspension. In influence factor test, we had carried out high temperature test(60℃), high humidity test(75 ± 5%) and strong light irradiation test(4500 ± 500Lx) respectively, and it was found that the character, sedimentation ratio,loss on drying, solubility, content and foaming rate of the dry suspension all had no significant change after ten days under the conditions of high temperature and strong light irradiation. However, under high humidity condition, the dry suspension would absorbed moisture and gained weight obviously, while its sedimentation ratio,solubility, foaming rate and content had little change. Besides, simethicone dry suspension packaged according to commercially available, had good stability, and the indexes of character, content, solubility, sedimentation ratio and so on, all had no significant change under the conditions of six months of accelerated test and six months of long-term test, and the long-term test is continuing.In the last part, the pharmacodynamic effects of simethicone dry suspension had been studied on the mice gastrointestinal inflation model. Firstly, we studied the influence of different doses of FOS and the different time after gavaging FOS on the flatulence model respectively, and finally chose 7.5 g·kg-1 of FOS to create the gastrointestinal flatulence model. Then 2 h after oral administration, the simethicone dry suspension after dissolved with water was given to investigate its efficacy.Meanwhile, SPSS 16.0 statistical software was used to statistically analyze the effect of different doses of simethicone dry suspension on the elimination of gastrointestinal flatulence. The results showed that the difference between the high(120mg·kg-1) and the middle dose(60mg·kg-1)group was not significant, and the two dose groups had significant difference compared to the low dose(30mg·kg-1)group, which indicated that simethicone dry suspension with the dosage of 60mg·kg-1 could produce significant defoaming effect to the mice gastrointestinal inflation model.