2 - Hydroxypropyl-¦Â-cyclodextrin Preparation Of Insoluble Drug Powder For Injection Of The Study

OBJECTIVE: To investigate the action of 2-hydroxypropyl-β-cydodextrin (HPCD) on increasing aqueous solubility of lipophilic drugs, cinnarizine and meloxicam were selected as typical drugs. By the use of HPCD, injectable powder preparations of the two drugs were developed respectively, without any organic solvent during the produced process. METHOD: Different ultraviolet spectrophotometry methods were set up to determine the aqueous solubility of the drugs at various pH with different amount of HPCD. The apparent stability constant (K_c) of inclusion complex was calculated by solubility isotherm method. After performulation study, neutralization method was selected to prepare drug solutions, and the two kinds of injectable powder were obtained finally by freezing -dried. X-ray diffraction, differential scanning calorimetry and infrared spectrum were used to identify inclusion complexes. Different HPLC methods were developed to analyze the drug during the test of quality and stability. Irritative, anaphylaxis, and haemolyticus tests were preformed to evaluate the injectable safety of the two preparations. Three different doses of HPCD in solutions were designed as 0 (Group A), formulation rate (Group B), 20 times of formulation rate (Group C), respectively, with the same dose of meloxicam (0.5mg/kg) in each group. The solutions were intravenous administrated to rabbits to evaluate whether the pharmacokinetic of drug was effected by HPCD. A HPLC method was developed to determine meloxicam in rabbit serum, and the pharmacokinetic parameter data was evaluated by 3P87 program. RESULT: The aqueous solubility of the both lipophilic drugs was highly improved at various pH by HPCD. By using HPCD, the concentration of cinnarizine and meloxicam could be 10mg/mL at pH3 and 5mg/mL at pH8, respectively. The specifications of the two preparations were 20mg/bottle (Cinnarizine for injection), and 7.5mg/bottle (Meloxicam for injection), respectively. The results of the quality and stability test showed the both productions met the criterion of Chinese Pharmacopoeia. The safety test proved the productions were safe to inject. It was assured in the identification assay that drug and HPCD had formed inclusion complexes. By Student's t test, no statistically significant difference (P>0.05) was found in the main pharmacokinetic parameters between Group A and Group B, Group A and Group C. CONCLUSION: The two injectable powder preparations, whose quality could be controlled well, were safe, active and stable. The pharmacokinetic of meloxicam was not effected by HPCD during the range of used.