Study On The Soft Capsules Of The Effective Fractions From "Antipyretic Analgesics Powder"

Background"Antipyretic analgesics powder" is an old famous medicine of a Professor named Zang Kun-Tang in my school. It had a significant effect for headache,fever and other symptoms caused by upper respiratory tract infection of exopathic typhoid through clinical testing for many years. But for the application in clinical in the form of powder, patients need a large dose, bad taste, get inconvenient to use and carry, at the same time learn from the health point of view does not conform to norms, so we should make secondary development using the new research methods.The prescription of "Antipyretic analgesics powder" is composed of Bupleurum, Notopterygium, Chen bacteria and Guizhi. Through preliminary works, the effective fractions from "Antipyretic analgesics powder" had been abstracted by means of the supercritical fluid extraction-Molecular Distillation (SFE-MD) technology, using orthogonal design test methods which had the track targets of analgesia experiments. The effective fractions had brown oily appearance, which were rich of Volatile oil and lipophilic ingredients by a preliminary assessment. By the GC/MS analysis, it showed that the major ingredients of the effective fractions were Cinnamaldehyde and para-ethoxyacetanilide.After abstraction, the effective fractions had a evaluation on pharmacodynamics and safety, the feasibility of exploitation was investigated, and the possible effect mechanism was also studied. The result showed that the effective fractions were safe and little toxicant. The effective fractions should have an upstanding development prospects.Exploration worth of the effective fractions was confirmed, and then we were supposed to study the pharmaceutics of them so as to explore a safe, stable, effective new traditional drug. The work contented the study of the soft capsules prescription, technology, stability, and quality criteria. Because of the characters of volatility, lipotropism and sensitivity to air, light and heat, the effective fractions were encapsulated in soft capsules which would enhance its stability.ObjectiveBased on the preliminary work, there are three main purposes on this subject of the study:1,Study on the quality control of the effective fractions from "Antipyretic analgesics powder";2,Study on the exploration of soft capsules of effective fractions from "Antipyretic analgesics powder";3,Study on the quality criteria of soft capsules of effective fractions from "Antipyretic analgesics powder";4,Study on the stability of soft capsules of effective fractions from "Antipyretic analgesics powder".Methods and Results1,The study on the quality control of the effective fractions from "Antipyretic analgesics powder"The ingredients of the effective fractions were determed by GC-MS. The finger print method was set up for the total of the effective fractions, and from which the Notopterygium and Guizhi were identified by TIC. The HPLC was applied for quantitative detection of cinnamaldehyde from the effective fractions. It is proved that the latter method is accuracy, repeatability, and high reproducible. The content of cinnamaldehyde was 6.521%. 2,Study on the exploration of soft capsules of effective fractions from "Antipyretic analgesics powder"Pre—experiment was employed to select the essential contents of soft capsules, then the capsule shells and content were prepared in the laboratory conditions. The capsule shells were immersed in the capsule contents at the room temperature and 40℃conditions, and then were taken out of for detecting disintegration on the 0 day, third day, tenth day and twentieth day. The comparison and data analysis were complied between the Group 1 of prescription (the capsules material of soybean oil) and the Group 2 of prescription (the capsules material of a mixture from soybean oil and effective fractions). The result showed that the differences were significant statistically (P=0.000, F=27.771) compared with two groups of prescription. Through the apparent data, it could be seen that disintegration time of the shells immersed in the effective fractions and in the mixture of effective fractions and peanut oil was longer than it in the peanut oil.For the shells sluggish disintegration problem appeared in the simulation experiment, the effective fractions were tried to be enfolded in theβcyclodextrin, which can get soft capsules and improve the stability. According to orthogonal survey conducted with the extraction rate and recovery rate of volatile oil as the index for the evaluation, we concluded the optimum inclusion technology.The results of the inclusion research were as follows:with the method of the saturating water solution, all factors had no significant differences (P=0.125,F=7.023;P=0.460,F=1.173;P=0.501,F=0.995), and the optimum preparation condition was A2:B3:C1 which means that the ratio of active fractions extract toβ-cyclodextrin(β-CD) was 1:8(g/g),the temperature was 40℃and the time was 2 hours. With the supersonic method, the supersonic time factor had the significant difference (P=0.013,F=73.402), and the water and effective fractions ratio factors had no significant differences (P=0.125,F=7.023;P=0.220,F=3.539). The optimum preparation condition was A1:B1:C2 which means that the ratio of active fractions extract toβ-CD was 1:6(g/g), the ratio ofβ-CD to volume of water was 1:15(g/ml) and the time was 2 hours. With grinding method, the effective fractions ratio and grinding time factors had significant differences (P=0.006, F=166.032; P=0.033, F=29.555), and the water factor had no significant difference (P=0.157, F=5.387). The optimum preparation condition was A2:B2:C1 which means that the ratio of active fractions extract toβ-CD was 1:8(g/g), the ratio ofβ-CD to volume of water was 1:4(g/ml) and the time was 2 hours.One more time, pre—experiment was employed to select the essential contents of soft capsules, then the capsule shells and content were prepared in the laboratory conditions. The capsule shells were immersed in the capsule contents at the room temperature and 40℃conditions, and then were taken out of for detecting disintegration on the 0 day, third day, tenth day and twentieth day. The comparison and data analysis were complied between the Group 1 of prescription (the capsule materials of soybean oil) and the Group 2 of prescription (the capsules material of a mixture from soybean oil and inclusions). The result showed that there weren't significant differences statistically (P=0.092, F=3.016) between two groups of prescription, which could means that the problem of disintegration got improved effectively and the stability of capsules was increased after the inclusion of effective fractions with theβ-CD which prevented the cross linking between the capsule materials and shells.We decided a final forming process based on the research on concentration of different types contents, different proportions of the molding material and the amount of lubricant agent. The best soft capsules formatting ratio of soybean oil and inclusion was 1.5:1, joined in 1% soybean phospholipids. On this way, the contents have good fluidity and suitable viscosity.3,Study on the quality criteria and stability of soft capsules of effective fraction from "Antipyretic analgesics powder"In the study on quality criteria for capsules, the finger print method was set up for the total of the capsules, and from which the Notopterygium and Guizhi components were identified by TIC. The HPLC was applied for quantitative detection of cinnamaldehyde from the capsules. We established the perfect quality criteria for the capsule.4,Study on the stability of soft capsules of effective fractions from "Antipyretic analgesics powder".The soft capsule's stability was determined by the above methods. Results indicated that the soft capsule is steady in three months.ResultsOwing to the oily, the effective fractions from "Antipyretic analgesics powder" possessed volatility and certain tastes. Compared with other solid dosage forms, soft capsule had the advantage of higher bioavailability, rapid absorption, stability, the ability of covering up the bad tastes and so on. Therefore, the research of soft capsules for the effective fractions was reasonable and feasible.Due to the shells sluggish disintegration problem appeared in the simulation experiment, the reason was guessed that the cinnamaldehyde from effective fractions was cross-linked with the capsule shells. So it is necessary to enfold the effective fractions into theβcyclodextrin through the inclusion technology, which can get soft capsules and improve the stability.After the research about inclusion technology, it could be seen that the optimum conditions with the grinding method can gain the high rate of inclusion and productivity, so they were satisfied. The optimum conditions with the saturating water solution method, just lower than the grinding one on the rate, were suitable, reliable and fit for mass production. Through the pre—experiment once more, the results showed that the problem of disintegration got improved effectively and the stability of capsules was increased after the inclusion of effective fractions with theβ-CD.After the research of the quality criteria and preliminary stability, we could get that the effective fractions capsules was controllable of quality and reliable of stability, which met the quality requirement of the capsules.It is feasible for exploring the soft capsules of ineffective fractions from "Antipyretic analgesics powder" after the results of this research. Then it will put the solid foundation for the study about the hospital new drugs and Traditional Chinese new drugs.