Development Of Self Micro-emulsifying Calcium Alginate Beads System With Poorly Water-soluble Drug Loading

Curcumin(CU) which is extracted from a Zingiberaceae plantpolyphenols has antioxidant, anti-inflammatory and anti-cancer properties.Many studies have shown that curcumin also has the pharmacologicaleffects of reducing the amount of cholesterol, anti-bacterial, promotingwound healing, anticonvulsant, anticoagulant, anti-tumor and preventingthe damage to liver.The poor water solubility and rapid metabolism ofCurcumin greatly limits its bioavailability in oral absorption process,thereby limiting its clinical application.Naftopidil (Naf) is a highly selective alpha1receptor antagonists,calcium antagonism and5-HT1A receptor agonism. Naf can effectivelylower blood pressure and has a lasting antihypertensive effect. There is nosignificant effect of the first dose and drug resistance. At the same time,Naf can alleviate prostate and urinary tract sympathetic nervous induced byα1A and α1D receptor, reduce prostate the internal pressure. Due to theadvantages given above, Naf is used in benign prostatic hyperplasia. Butbecause of Naf insoluble in water, it is difficult to absorb and unstable in the body, thus it limits the naftopidil in clinical applications as well asfurther research.To improve the solubility of poorly soluble drugs, the selfmicro-emulsifying drug delivery system has been developed. But they areusually produced in liquid formulation, which is packed in soft capsules orhard gelatin capsules, and thus making the production process complicated,high-cost, easier compatible of formulation ingredients with the capsuleshell, the possible occuriance of capsule leakage during the long-termstorage, few choice of dosage forms. To overcome these shortcomings, andcombine the advantages of SMEDDS and solid formulation, CU and Nafwill be invested as model drugs in this paper. The most importantly, thepreparation methods of CU-SMEDDS-ALG-beads andNAF-SMEDDS-ALG-beads will be also discussed, in order to improve thesolubility and oral bioavailability.Part I Development of curcumin self-emulsifying calcium alginatebeadsUV determination method of CU was established. while CU dissolvedin50%ethanol, the maximum detection wavelength was424nm, theabsorbance showed a good linear relationship between the concentration ofthe drug in0.5μg/mL~6μg/mL concentration range. Its intra-day precision and recovery are in line with the methodological requirements.CU-SMEDDS-ALG-beads is prepared by dropwise method. Drybeads are obtained by thermostatic drying and the freeze-drying methodwhich have good fluidity and appearance.Particle size and zeta potential of the CU-SMEDDS-ALG-beads.The particle size of CU-SMEDDS-ALG-beads is less than100nm.CU-SMEDDS-ALG-beads were detected by DSC. The drug releaseprofiles of CU-SMEDDS-ALG-beads were studied by shaking water bath.Effects of concentration of ALG, the concentration of calcium chloride, theratio of liquid SMEDDS/ALG solution on the drug release ofCU-SMEDDS-ALG-beads release were studied.Part II The development of naftopidil self micro-emulsifyingcalcium alginate beadsEstablish UV method for the determination of Naf。The detectionwavelength of Naf in50%ethanol was283nm. In concentration range of5.0μg/mL~40.0μg/mL, absorbance and concentration showed a goodlinear relationship. Its intra-day precision and recovery are in line with themethodological requirements.Naf-SMEDDS-ALG-beads were prepared by using the method ofdropwise. Dry beads which were obtained by a thermostatic drying method and the freeze-drying method have good fluidity and appearance.Particle size and zeta potential of the Naf-SMEDDS-ALG-beads,particle size is less than100nm. Naf-SMEDDS-ALG-beads were analysedthrough DSC scan, Naf Naf-SMEDDS-ALG-beads in the presence of stateare conducted in investigations. In vitro release study is aim at studying theeffect of ALG concentration, the concentration of calcium chloride, theproportion of liquid SMEDDS/ALG solution on the drug release ofNaf-SMEDDS-ALG-beads.Part III Study on pharmacokinetics of Naf-SMEDDS-ALG-beadsin ratsHPLC method for the determination of Naf was built. The peak timeof Naf was about4.8min with a good shape. The plasma would not effectthe determination of the drug. The concentration range is10-1600ng/ml,which had a good linear relationship, the standard curve equation was A=0.4717C+1.3536R=0.9998. Extraction recovery, recoveries intra-dayprecision were in line with the methodological requirements.The results showed that the t-max advance, C-max increased2.64times and the AUC in0-24h increased4.53times whenNaf-SMEDDS-ALG-beads compared with non-SMEDDS-ALG-beads. Theresult indicated that Naf-SMEDDS-ALG-beads could improve oral bioavailability. While NAF-SMEDDS compared withnon-SMEDDS-ALG-beads its release time was much earlier. Tmax, Cmaxincreased3.20times, the AUC0-24hincreased6.67times.Self micro-emulsifying calcium alginate drug delivery systemprepared in this study can significantly improve the solubility of poorlysoluble drugs, and oral bioavailability. In this way, we have realized that aliquid preparation has been transformed into solid formulation. In conclude,CU and Naf show excellent prospects in the clinical.