The study of excipients’ influence on Clopidogrel releasing from the rectal suppositories

Abstract

Such cardiovascular pathologies as ischemic disease of heart and brain, occlusive diseases of peripheral arteries are the most frequent causes of morbidity, mortality and disability of population in the world.

The united pathologic process – atherosclerosis underlies all these diseases. Atherothrombosis is its clinical manifestation; it is the base of overwhelming majority of acute coronal, cerebral and peripheral arterial involvement.

Thrombosis in cardiovascular system is a multifactorial process. The important role belongs to platelet activation that is the basis for clinical administration of antiplatelet drugs for primary and secondary preventive measures in thrombotic complications. Existent close correlation of atherogenesis and platelet formation pathogenetically proves prescription of antiplatelet drugs both for treatment, and for primary and secondary preventive measures.

In recent years Clopidogrel plays the lead role as a medication with the mechanism of platelet anti-aggregation. It belongs to the pharmacological group of adenosine receptor antagonists which suppress the platelet activation by the selective binding of ATP with specific receptors. Besides Clopidogrel has strong polyvalent antiplatelet effect. Also using of Clopidogrel leads to reliable decrease of triglycerides’ level and optimization of other indexes in lipidogram.

On Ukrainian pharmaceutical market Clopidogrel is presented in domestically produced and imported coating tablet form.

Rectal administration of Clopidogrel is alternative to oral use because it allows to decrease the dose of active pharmaceutical ingredient at the expense of bioavailability increasing and to minimize the rise of side effects risk.

The aim of this work is the study of influence of excipients used in suppository manufacturing (bases and surface active substances) on biopharmaceutical properties of Clopidogrel rectal dosage form.

Materials and research methods. As carriers for Clopidogrel rectal dosage form the suppository bases and surface active substances widely used in manufacturing and compounding of semisolid dosage form and described in literature were investigated. Suppositories were made by the fusion method. Concentration of surfactants in all compositions was 2%, clopidogrel – 0,075 g in one suppository. Investigation was carried out by the 2-factors dispersive analysis with repeated observations.

Clopidogrel was added in suppository by the suspension type after thorough pulverization of medical substance with equal amount of ethyl alcohol, after that with some of the base and following adding of obtained mixture to the all melted base.

Clopidogrel releasing was chosen as the first step of bioavailability investigation. Clopidogrel releasing from suppository was studied using the equilibrium dialysis by Kruvchinsky at temperature 37 ± 0.5 °С through a cellophane semipermeable membrane – film «Kuprofan» under the State Standard GOST 7730 in the nine positional Franz cell apparatus (producer PermeGear Inc., USA). Ethyl alcohol was chosen as a dialysis medium considering the solubility of Clopidogrel. Concentration of released Clopidogrel after 30 minutes of the dialysis was determined by spectrophotometric analysis.

Results. It was established that the sort of the base and surfactant have significant influence on Clopidogrel releasing from rectal suppository.

Conclusions. It was revealed that the sort of base has the greatest influence on Clopidogrel releasing from rectal suppository. Variance analysis has shown optimal Clopidogrel releasing from rectal suppository with composition of polyethyleneglycol base and twin-80.