Studies On Iloperidone Hydeoxypropyl-β-Cyclodextrin Inclusion Complex Injection

Iloperdone is a psychotropic drug belonging to the class of atypical antipsychotics. Its chemical name is4’-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3’-methoxyacetophenone, molecular weight426.48, it is practically insoluble in water, in2009, Iloperdone(Fanapt) was supplied as a tablet defined for oral administration, which was approved by the Food and Drug Administration(FDA) for sale in the United states (there is no other formulations in the market)[1]. Iloperidone was rapidly absorbed in all animal species tested following oral and i.v. administrations, but its bioavailability was very low due to a significant first-pass effect, oral bioavailability was<1%in rat,5%in mouse,19%in both rabbit and dog, and approximately36%in humans. Iloperidone used for treatment of schizophrenia with lesser adverse effect and it also effectively used to treat acute schizophrenia had been report. The aim of this study is to prepare an inclusion complex of iloperdone and HP-β-CD to improve its aqueous solubility so that it can meet the requirement of clinical parenteral administration, and enhance the absorption rates and bioavailability, reduce drug dose.The object of the present study were:(1) The analytical method was developed to determining the content of Iloperidone; Investigation the preparation technique and screening optimized formulations of Iloperidone-HP-β-CD inclusion complexes;(2) Character the inclusion complexes;(3) Prepare Iloperdone-HP-β-CD inclusion complex injection and perform the stability experiment;(4) The muscular stimulation of Iloperdone-HP-β-CD inclusion complex injection;(5) Pharmacokinetic study of Iloperdone-HP-β-CD inclusion complex injection in beagle dogs.The analytical method based on UV spectrophotometry was developed to determining the content of Iloperidone, and then calculate the inclusion rate. Iloperidone-HP-β-CD inclusion complex was prepared by grinding method, ultrasonic method and solution stir method respectively. The results showed that solution stir method was suitable for the preparing of Iloperidone-HP-β-CD inclusion complex. The optimized formulation and technique of prepare Iloperidone-HP-β-CD inclusion complex was obtained by the L9(34) orthogonal methodology, and the inclusion rate of the product was99.34%.Prepare iloperdone-HP-β-CD inclusion complex solution by solution stir method, and the inclusion complex in solid state was obtained by freeze-drying; Drug-cyclodextrin interaction in solution were investigated by phase solubility diagrams and the complex were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry techniques (DSC) and solubility method, the result indicated that iloperdone was able to form an inclusion complex with HP-β-CD.Prepare iloperdone-HP-β-CD inclusion complex injection, and then assessed the stability. In the stability experiment, the effects of the high temperature and strong light on the inclusion complex injection were studied, also the accelerated experiment was conducted. The result indicated that inclusion complex injection was stable on hight temperature but the stable could be influenced by the strong light; after accelerated experiment, the inclusion complex injection was still relatively stable.The muscular stimulation test of Iloperdone-HP-β-CD inclusion complex injection was perform in rabbit, The result suggested that the injection had no significant stimulation on muscles.The pharmacokinetic of iloperdone tablet and iloperdone inclusion complex solution were evaluated after Oral administration and muscular injection in dog, respectively. An HPLC method was established to determine the content of Iloperdone in plasma, the serum concentration-time data were analyzed by non-compartmental model. The result show that in comparison with oral iloperidone tablet, the injection HP-β-CD complex gave higher plasma levels of iloperidone, the Cmax of iloperidone-HP-β-CD inclusion complex was3.29-fold higher then iloperidone tablet, the t1/2and the tmax of iloperidone-HP-β-CD inclusion complex were also decreased compared with iloperidone tablet, further, the AUC(0-∞) of complex were about1.43-fold higher then the table. All the result above indicated that faster in vivo absorbtion and higher bioavailable of iloperidone-HP-β-CD inclusion complex injection.Based on the results, it can be concluded that the studies on iloperdone-HP-β-CD inclusion complex excellently reach the goals that we predicted. The preparation method is simple and convenient. The stability test also indicated that the inclusion complex injection were possibly stable enough. Iloperdone-HP-β-CD inclusion complex injection have no stimulation on muscles, the absorption rates and bioavailability of Iloperidone were significantly enhanced.