Study On Nanocrystal Preparations Of Nitrendipine

Nitrendipine is a calcium channel blocker,and used as an antihypertensive drug.It is a BCS(Biopharmaceutical classification system)class ? compound which is practically insoluble in water and has good membrane permeability.The rate-limiting step of absorption for nitrendipine is the low dissolution rate,which is responsible for the poor oral bioavailability.In the present study,high pressure homogenization method(HPH)was employed to prepare nitrendipine nanocrystals to improve the in vitro dissolution rate and in vivo bioavailability.Firstly,single factor study was employed to investigating the preparation process,and a simple and reliable preparation process was established.The effects of pretreatment,type of stabilizer,the concentration of stabilizer,the homogenization pressure and the homogenization cycles were investigated systematically.Also the morphology,physical properties and the in-vitro dissolution of the nanocrystals were investigated.The results indicated that aging and crushing existed simultaneously during the high pressure homogenization process,when precipitation was used as pretreatment.Using the single factor method,the optimal process parameters were obtained:the drug concentration in acetone was 100 mg/ml,the PVA concentration in water was 1 mg/ml,precipitation temperature was set at 10 ?,and the pre-suspension was homogenized for 20 cycles at 100 MPa.The mean particle size of the obtained nanocrystals was about 175 nm and flaky in shape.Both differential scanning calorimetry(DSC)and X-ray diffraction(XRD)analysis indicated that nitrendipine was present in crystalline form.Solubility study indicated that the equilibrium solubility of nitrendipine increased with the decreasing particle size of nitrendipine.And the melting point of nitrendipine decreased with the decreasing particle size of nitrendipine.The long-term stability was still a big challenge for nanosuspensions.So spray drying,which is a cost-effective method and very popular in industrial situations,was employed to solidify the nanosuspensions.The in-vitro and in-vivo studies of the dry nanosuspension were carried out.The results indicated that the addition of the carriers(lactose and mannitol)did not influence the particle size of the nanocrystals.The obtained dry powders could be easily re-dispersed into water without aggregation or agglomeration,and the particle size was similar to that before spray drying.The addition of the carriers increased the flowability of the dry nanosuspension.Both differential scanning calorimetry(DSC)and X-ray diffraction(XRD)analysis indicated that nitrendipine was present in crystalline form.The long-term stability study showed that the particle size of the nitrendipine nanocrystals remained constant with good re-dispersability over the 1 year storage period under ambient conditions.The in-vitro dissolution study indicated that nanocrystals significantly improved the dissolution rate of nitrendipine,and the enhancement could be attributed to the increasing surface area,not solubilization or wetting effect of the additives(PVA and mannitol)on the drug.The plasma drug concentration profiles of the nanocrystals showed a significant improvement in drug absorption compared with the physical mixture and the commercial tablet.The relative bioavailability of dry nanosuspension and the physical mixture were 1018.93%and 23.64%,respectively,compared with the commercial tablet.Then,an oral disintegrating film(OD-film)containing nitrendipine nanocrystals was prepared,and the in vitro and in vivo study were carried out.A Box-Behnken design(BBD)was created in SAS JMP(?)to investigate the effect of film components on the film characteristics.The established model could be used to predict the disintegration behavior and the tensile strength of the OD-Films.Based on the above-mentioned experiments,two OD-films containing nitrendipine coarse powder or nitrendipine nanocrystals were prepared.For the prepared OD-films,the thickness were about 200 ?m and could disintegrated within 1 minute.A rapid dissolution of the OD-film containing nitrendipine nanocrystals was observed,while,the dissolution rate was quite slow for the OD-film containing nitrendipine coarse powder.All the films disintegrated completely within 10 seconds during the in vitro dissolution study,which means the difference in the dissolution rate was caused by the difference in the crystal size.These results indicate that the OD-film containing nitrendipine nanocrystals is a suitable dosage form for rapid release of water insoluble drugs.The in-vivo study in rats indicated that oral administration of the OD-film containing nanocrystals could further increased the bioavailability,and the relative bioavailability was 140%compared to intragastric administration of the OD-film containing nitrendipine nanocrystals.Finally,chitosan,one of the most promising biopolymers for drug delivery,was employed to modify the nitrendipine nanocrystals,and the in-vitro and in-vivo studies were carried out.After the nanocrystals was modified with chitosan,the zeta-potential changed from negative to positive,however,the particle size remained the same.Chitosan also slowed down the dissolution rate of nitrendipine.The in-vivo study in rats indicated that the tmax of nitrendipine was significantly delayed and the AUC0.24 improved significantly,when oral administration of the chitosan modified nanocrystals,compared with oral administration of the initial nanocrystals.However,the Cmax of nitrendipine did not show any difference between the modified and un-modified nanocrystals.