Studies On The Quality Control Of Ozagrel Hydrochloride And Its Pharmacokinetics

Ozagrel is a new type of anti-asthma drug, Pharmacological studies show that ozagrel is a strong inhibitor of thrombroxane 2. To develop it into a new drug, a systematic study was carried out on this drug. First, in order to make sure the quality of ozagrel raw material, a series of methods were developed for the quality study of ozagrel raw material. Then, according to the physical and chemical properties, the formulations for tablets and capsules were designed and optimized. The stability testings were carried out to make sure that these formulations were appropriate and to find the suitable storage conditions. Also, the pharmacokinetics of ozagrel in rats was studied to provide reference for clinical study.1. Study on the quality controls of ozagrel raw material and its formulationsAccording to the pharmacopiea and new chemical drug research guidelines, the quality control methods for the raw material were studied. Titration method was used for the content determination. A reversed-phase ion pair HPLC method was used for the study of intermediates and degradation products of ozagrel. Ozagrel may have four kinds of intermediates brought by synthetic process. Ozarel and the intermediates can be separated by the HPLC method, and the acid and base degradation products can also be separated by the same method. The methods for the quality control of ozagrel tablets were set up. A UV method was used to determine the dissolution, a HPLC method was used to determine the ozagrel tablets and an ion pair HPLC method was used to determine the degradation products. According to the quality control methods of ozagrel tablets, the similar methods for the quality control of ozagrel capsules were set up.2 The formulation study of ozagrelThe formulation is designed according to the chemical and physical properties of ozagrel. Considering the excipients available and the requirement of tablets, the interaction study between ozagrel and excipients was carried out. Those excipients which do not interacted with ozagrel were used to design a formulation, the formulation was further optimized. A tablet formulation with good appearance, hardness and dissolution was established. The stress testing was performed on the tablets, and the result shows that ozagrel tablets were stable under high temperature, high humidity and light. Referring to the development of ozagrel tablets, a formulation for ozagrel capsule was designed and optimized. Finally, a capsule formulation with good dissolution was established. The stress testing was performed on the capsules, and the result shows that ozagrel capsules were stable under high temperature, high humidity and light.3 Studies on the pharmacokinetics of ozagrel in ratsA simple and sensitive HPLC-UV method was established to determine ozagrel in rat plasma. The separation was performed on a C₁₈ reversed-phase column with detection wavelength set at 300nm. The calibration curve was linear over the ranges of 0.1～50μg·mL^-1 The limit of quantitation was 0.055μg·mL^-1. Within-day precisions were 2.2%～5.0%, Between-day precisions were 3.3%～7.0%, The accuracy expressed by RE were 0.2 %～8.6%, This method was successfully applied to investigate the pharmacokinetics of ozagrel in rats.Following a single dose oral administration of ozagrel at a dose of 20 mg·kg^-1, the pharmacokinetics were obtained. It was shown that the absorption of ozagrel after an oral administration was rapid. Cmax of ozagrel in rat plasma was 6.0μg·mL^-1 and Tmax was 0.72h. AUC0～t was 473.8±88.5μg·min·mL^-1, The plasma concentration after oral dose administration was fitted to a one-compartment model.