Study And Prepareation Of The Compound Asa And5-Ismn Sustained-Release Tablets

Cardiovascular disease is the world’s serious diseases which has posed a threat to human health due to its high morbidity and mortality rates. And what’s worse, it is more and more prevalent among young people. Angina Pectoris and myocardial infarction is one of the most serious acute cardiovascular diseases. Isosorbide mononitrate (5-ISMN), a vasodilator, and aspirin (ASA), an antiplatelet drug, are the mostly used medicines for angina pectoris, myocardial infarction disease. So the compound sustained-release tablets of ASA and5-ISMN developed in this article can effectively play a synergistic effect and advantages of each. As a result, the compound tablets can not only better prevent angina pectoris and experimentally myocardial infarction, but also prevent miss-taking and stop-taking aspirin phenomenon occurs in the middle.In this topic, ASA was made into sustained-release tablets after being prepared into enteric pellets, which can effectively contribute to overcome the gastric mucosal hemorrhage, ulcers and other side effects caused by long-term use of ASA. Besides, the compound sustained-release tablets have good reproducibility of in vitro release, high bioavailability, small individual differences and other advantages of pellets preparation. Furthermore,5-ISMN was prepared into sustained-release tablets to make drug sustained-release, eliminate of peak-valley phenomenon, extend action time, reduce the frequency of medication, low side effects and improve the safety and compliance of the drug for patients. This research mainly involves preparation of ASA enteric-coated pellets and tablets, preparation of5-ISMN sustained-release tablets, preparation of compound sustained-release tablets of ASA and5-ISMN, in vitro drug-release studies and stability studies.1. Preparation of Aspirin enteric-coated pellets and tabletsThe main evaluation indicators of ASA enteric-coated pellets and determination methods were established. And ASA’s release rate and content were determined by the method of UV spectrophotometric. The results of methodological study showed that the method is accurate and reliable, which provides theoretical basis and data support to ASA enteric-coated pellets formulation selection and process optimization.ASA enteric-coated pellets’formulation was studied in this paper. On the basis of ASA’s physical and chemical properties, ASA pellets was prepared by the method of powder stratification. Based on the evaluation target of the pellets’characters, disintegration time and dissolution, the best prescription and process of the pill-core were selected through single factors test and orthogonal design. With the evaluation index of ASA’s content and its release in O.1mol/L HCl and pH6.8PBS, the enteric-coated material and coating technology were studied to select the best prescription and process of ASA enteric-coated pellets. On the basis of tablets’ hardness, friability, content and release rate, the pellet-tablets’formulation and process were studied. Results showed that ASA pellets can be prepared by stratification of powder core. The prepared pellets have a round surface and friability of only0.1%around. Furthermore, this method is easily operated and the preparation process is stability with a good reproducibility.ASA enteric pellets prepared by centrifugal pill machine have a particle size from0.4mm to1.0mm, good fluidity and high compressive strength and meet the requirements of tabletting. And various performance indicators of the prepared tablets’are fit for the requirements of the tablets. The drug content is90%～110%to the labeled amount. The vitro release rate is less than1%in0.1mol/L HCl and more than95%in pH6.8PBS, which are all in line with standards.2. Preparation of the sustained-release tablets of Isosorbide MononitrateThe main evaluation indicators of5-ISMN sustained-release tablets and the determination methods were established. And the method of UV spectrophotometric was developed to determinate the in vitro release rate and drug content. The methodological study indicated that the method is accurate, reliable and suitable for the research of formulation and process of5-ISMN sustained-release tablets’.In this research, the formulation and preparation process of5-ISMN sustained-release tablets were studied. Based on the physical and chemical properties of5-ISMN,5-ISMN sustained-release tablets are prepared by the technology of hydrophilic gel-matrix. Firstly, the sustained-release material and the filling materials are studied. Based on this, the best formulation and preparation process of5-ISMN sustained-release tablets are selected by single factors test and orthogonal design with the main indicator of the release rate and drug content. Results revealed that the preparation technology of hydrophilic gel-matrix is easily operated, stability and reproducible. The sustained-release tablets with content of90%-110%to the labeled amount release drug20%-45%,30%-65%,50%-75%and more than75%to the labeled amount at2h,4h,6h and10h, respectively. They are all in line with standards.3. Preparation and study of the compound sustained-release tablets of Aspirin and Isosorbide MononitrateThe compound sustained-release tablets of Aspirin and Isosorbide Mononitrate are prepared by the technology of double-layer tablet according to the above formulation and preparation process. Results showed that the compound sustained-release tablets can be easily prepared by double-layer tablet press with two kinds of particles prepared by two different processes. This preparation process is simple, stability, reproducible and suitable for industrial production.The two components’contents, release rate, free salicylic acid and its related substances are determined by the method of HPLC. The HPLC method has high sensitivity and selectivity. And it is suitable for the quality control of the compound sustained-release tablets of ASA and5-ISMN. Three batches samples of self-made revealed that the preparation process is reliable and can meet the established requirements.4. In vitro release and stability research of the compound sustained-release tabletsIn this article, the in vitro drug release of self-made sustained-release tablets are researched and results indicate that the in vitro release profile meets the requirements of Enteric-coated preparation’s. The in vitro release profile of the compound sustained-release tablets followed Higuchi equation. The results fitting to Peppas equation and release results demonstrated that the compound sustained-release tablets released drug by the diffusion of drug and the dissolution of skeletal material.Stress testing, accelerated testing and long term testing of self-made compound sustained-release tablets were studied. Results showed that salicylic acid’s content and related substances of the compound sustained-release tablets have increased higher under the condition of92.5%RH. Otherwise, the tablets have no significantly changes under the conditions of high temperature (60℃) and strong light (4500Lx±500Lx) compared with the0-day data. Thus the tablets should be stored in closed containers due to their stability on light and heat conditions and sensitivity to wet conditions. After accelerated testing investigating for6months, the related substance has rise a little, but meet quality requirements of the standard yet, the other indicators have no significantly changes. By long term testing investigation for9 months, its appearance, content, release rate and the related substance have no obvious changes. Further study was needed in order to determine the shelf life as the insufficient time of investigation.To sum up, this compound preparation of ASA and5-ISMN sustained-release tablets have a reasonable formulation, feasible process, controllable quality as well as good stability. In vitro elease of ASA and5-ISMN meet the requirements of the enteric-coated preparations’and sustained-release preparations’, respectively. The compound sustained-release tablets of ASA and5-ISMN developed in this article can full play their synergistic action and advantages of each, which will contribute to prevent angina pectoris and myocardial infarction better. So the compound tablets have good social significance and application value in the treatment and prevention of cerebrovascular diseases.