Development Of Aspirin/ Extended-release Dipyridamol Capsules

Platelet conglutination, aggregation and thrombosis are the important pathogenis due to ischemic cerebrovascular diseases. It has been accepted that the interaction between platelets and vassal endodermis is the main factor forming thrombosis. The intervening of platelet abnormity function has become one of the leading measures to effective prevention and cure ischemic cerebrovascular diseases.Because of cheap cost, good curative effect and less side effect, aspirin is the most widely recognized and used antiplatelet drug among the numerous antiplatelet agents. Aspirin inhibits thrombosis by irreversible inhibition of platelet cyclooxygenase in arachidonic acid metabolic pathways. Platelet activation is a very complex process. Multiple receptors and mediators are involved in the activation response, release reactions. The arachidonic acid metabolic pathways is one of the ways to platelet activation, furthermore, it is likely to producing aberrance in metabolic pathways. The combination of antiplatelet drugs, which have different mechanisms of action and can inhibit multistage of platelet activation, has become an important direction of investigation and therapy of antiplatelet drugs. As a phosphodiesterases inhibitor, dipyridamole inhibits platelet activation by activating adenylate cyclase. increasing cyclic-3', 5'-adenosine monophosphate (cAMP) creation as well as reducing it decomposition. It becomes the theoretical base in compound of dipyridamole and aspirin that two medications accommodate platelets function and inhibit thrombus development in different phases and ways.Combine use and compound preparation of dipyridamole and aspirin, usually in a routine preparation form, have been used in clinic. The problem of a few drug dosages, reasonless of compound (dipyridamole 25mg, aspirin75mg) and so on lead to unperfect compound curative effect and relevant side effect, thereby distinctly limit in the actual use.It is discovered, via mechanism of action and characteristic of dipyridamole and aspirin, that combination of dipyridamole lOOmg and aspirin 12.5mg, moreover, aspirin absorption ahead of large numbers of dipyridamole by 40~70min, can acquire better curative effect. Therefor, it is requisite to design a compound preparation of dipyridamole and aspirin, and to prepare aspirin/ extended-release dipyridamol capsules, containing dipyridamole in an extended-release form and aspirin in an immediate-release film-coated tablet.In order to cooperate with immediate-release of aspirin and continuously maintain effective plasma concentration of dipyridamol, lOOmg extended-release dipyridamol preparation is designed that 40% dosage has sustained-release in stomach and 60% dosage has immediate-release in small intestine. Dipyridamol is a feeble alkaline compound, being diffluent in acid and indiscerptible in solution which pH more than 4. Dipyridamol slow releases in stomach is considering by the mothod of coating gastro-soluble sustained-release material. Because dipyridamol is indiscerptible in litmusless enteric solution, it is needed to solve the solubility problem for achievement dissolution in enteric solution and immediate-release in small intestine.The method of coating tartaric acid out of inner pellets is better way to increasing dipyridamol solubility in small intestine and to accomplishing the immediate-release of dipyridamol in small intestine. The optimum prescription and preparation of enteric-soluble immediate-release pellets is obtained by orthogonal test of dosage of tartaric acid, Eudragit? SI00 and Eudragit* LI00-55. Sequentially, a design of further coating gastric-soluble sustained-release of dipyridamol out of the enteric-soluble immediate—release pellets has finished, in order to produce the homogeneous pellets.Dipyridamol solubility in gastric juice is controlled by selection of Eudragit RSI00 and Eudragit* RL100 as block material. According to the characteristic of dipyridamol, that is easy soluble in gastric juice, the optimum prescription and preparation of gastric-soluble sustained-release pellets is obtained by orthogonal test of dosage of Eudragit? RSI00, Eudragit? RL100 and triethyl citrate. After theselection test, a sustained-release dipyridamol pellet (40% dosage as gastric-soluble sustained-release and 60% dosage as enteric-soluble immediate-release in every single capsule) has obtained.Aspirin is designed to be 12.5mg film-coated tablets on a cooperation therapy basis. Aspirin is unstable in water and easy to decompose into salicylic acid. A series of selection test about stable agent, adhesives, diluents of aspirin tables, was accomplished under controlled the content of salicylic acid. Finally, the optimized prescription composed with tartaric acid (as a stable agent), PVP k30 (as an adhesives), lactose, micro cellulose and starch (as diluents) was chosen. Meanwhile, the optimum preparation method is also selection, including the humid producing granule method, the fundus coating agent with polyacrylic resin II and the coating agent with HPMC.The optimum preparations of extended-release dipyridamol pellets and aspirin film-coated tablets have been finished in largescale. Then, 12.5mg aspirin film-coated tablet and lOOmg extended-release dipyridamol pellets are together filled in a single capsule. Results show that the preparation method is available to control the quanlity, the reproducibility and fit for a largescale production. The aspirin/extended-release dipyridamol capsule has the similar delivery characteristic compared to the foreign reference preparation. The stability test data of three middle-scale batchs indicate that aspirin/extended-release dipyridamol capsule is stable.The bioavailability of the aspirin/extended-release dipyridamol capsules in healthy volunteers were carried through compared to the commercialized dipyridamole tablets and aspirin enteric-coated tablets. The result shown that the absorption rate of aspirin in the aspirin/extended-release dipyridamol capsules is faster than the reference preparation, but the absorption extent is similar to each other. The bioavailability of dipyridamol in the aspirin/extended-release dipyridamol capsules has the similar extent compared to the reference preparation, and displays the characteristic of sustained-release preparation in single-dose and multiple-dose study. The aspirin/extended-release dipyridamol capsules, twice a day, has a bioequivalence compared to the same dosage of commercialized dipyridamole tablets and aspirin enteric-coated tablets, thrice a day. It is indicated dipyridamol in the aspirin/extended-release dipyridamol has an enterohepatic cycling characteristic, and has higher plasma drug concentration after 14h by orally, result from theconcentration-time curve of single-dose administration. It is recommended that the aspirin/extended-release dipyridamol capsules be administrated by once a day.