Study On The Inclusion Complex Of Barnidipine And Buccaladhesive Tablets

Barnidipine hydrochloride is a novel 1,4-dihydropyridine Ca²⁺ antagonist, the first single optical isomers of which widely used in the treatment of high blood pressure possessing potent antihypertensive activity .This drug stereospecifically binds to the binding sites of vascular smooth muscle cell membrane potential of the calcium channel, they produce lasting and significant antihypertensive effects by inhibiting calcium influx in these cells. Barnidipine hydrochloride has strong liposolubility , low water-solubility and low oral bioavailability. In this study, inclusion technology was used to improve the dissolution and stability performance of the insoluble drugs Barnidipine hydrochloride(BN), and thus to increase its bioavailability. Additionally, the marketable slow-release formulations, buccaladhesive tablet, was prepared, which improved the bioavailability.In the present experimental preparation ,we select hydroxypropyl-β-cyclodextrin for the inclusion material ,use ultrasonic and freeze-drying technologies to prepare the inclusion complexation of Barnidipine hydrochloride-hydrochloride -β-cyclodextrin ,which Can significantly increase the solubility and stability of Barnidipine hydrochloride. The UV method was selected to determinate the content of the inclusion complex. The result of methodology studies showed that these methods are simple and quick,repeatability and accurate. The determination of inclusion and phase solubility studies have shown that molecular guest-host inclusion complex is 1:1. X-ray diffraction suggested that the inclusion complexation of Barnidipine hydrochloride-hydrochloride -β-cyclodextrin existed of the amorphous, and had connection with the change of the parameter, such as the spacing of crystal lattice, the grain size and orientation of the crystal lattice etc. Differential scanning calorimetry showed that inclusion complex and physical mixture of the energy changes with temperature differences. Fourier transform infrared could confirmed that there were some interaction between the carriers and barnidipine hydrochloride in the process of forming the inclusion complex. SEM visualizedly confirmed new form of the solid dispersion, different from that of crude drug and that of the physical mixture. Through the integrated score of drug loading and encapsulation efficiency, optimization of preparation process by the orthogonal design. And then the optimized conditions were that molar ratio of BN: HP-β-CD was 1:2, the reaction time was 40 min and the Ultrasonic power was 90%.The dissolution rate of the inclusion complex made by the optimized preparation process increased significantly.On this basis,buccaladhesive force, Barnidipine hydrochloride release rate and the flowability of tabletting materials were selected as the main objectives of the study . A prescription screening was carried out. At the beginning, single factors were inspected, such as the kinds of adhesive materials, the lubricants and their dosage for both inside and outside layer. Then a further four factors and three levels orthogonal experimental design was adopted for the optimization of the dosage of adhesive materials and lubricants. The ultimate prescription was determined: the inside layer contained the inclusion complexation of Barnidipine hydrochloride-hydrochloride -β-cyclodextrin32mg (equivalent to BN 5mg) , carbopol 934P 16mg, HPMC4mg;the outside layer contained carbopol 934P24mg,HPMC24mg and Magnesium Stearate 0.1% (100 mg/tablet). The preparation and process was inspected after determining prescription. Besides three batches sample was produced in advance in order to study quality standards, quality inspection and stability test. The sample content uniformity, process repeatability, and in vitro release in almost 8 hours.On quality evaluation of Barnidipine hydrochloride buccaladhesive tablets, the HPLC method which determinates the concentration of Barnidipine hydrochloride was established. The results of stability determination tests showed that buccaladhesive tablets was more stable at 60℃high temperature, but the concentration of Barnidipine hydrochloride in buccalashesive tablets reduced significantly in illumination condition and in 75% humidity conditions, which proved that the illumination and humidity showed impact to quality, and thus suggested that buccaladhesive tablets should be packed in sealed dark condition. The accelerated tests of stability shown that the preparation was stable, the drug content of the buccaladhesive tablets had little change during the accelerated experiment . It fit the requirement by Chinese Pharmacopeia. It holds the promise of becoming a new preparation for clinical in the future.