The Research Of Nanocrystal About Oral Drugs Using Protein As Stabilizer

With the development of high-throughput drug screening technology and testing technology, more and more valuable drug candidates have been found. However, due to the insoluble problem, many drug candidates have been abandoned reluctantly by scientists. How to solve the problem of poor solubility of drugs to put more drug candidates into clinical use, particularly those both insoluble in oil and water, become a very important issue. In this article, a way of improving the insoluble problem of oral drugs is studied which applied nanocrystal formulation technology and milk protein as the carrier. The process is simple and suitable for industrial applications. Itraconazole, somcl-9112 and curcumin is selected as model drugs, two major milk protein-casein and whey protein are choosed as stabilizers, high pressure homogenization-fast film evaporation technology are used in this research. In the study, investigation of temperature, pressure, time, number, concentration and other parameters are obtained aiming to get small particle size(about 200 nm), uniformed particle size distribution with simple process of production, high drug loading and enhanced solubility of drugs. In vitro dissolution and pharmacokinetic experiments of itraconazole and somcl-9112 show that the system improved drug dissolution and bioavailability. The major results are as follows:(1) Preparation of protein. First, the purification of casein, aimed to dissolved in water directly. Secondly, casein were modified to give the succinylated casein and acylated was reached more than 95%. Lastly, using isoelectric precipitation method to obtain ?-lactalbumin, ?-lactoglobulin from whey protein. The five kinds of milk protein as stabilizers were: purified casein, succinylated casein, whey protein, ?-lactalbumin, ?-lactoglobulin.(2) Processing optimization. Optimized conditions were as follows: dissolved the drug with a mixed solvent of chloroform and ethanol, dissolved protein in water to a suitable concentration. Mixed oil and water with high shear, high-pressure homogenized and film evaporated to give nanosuspension. Finally, freeze-dried to get protein-drug delivery systems. There were little differences between different proteins and pharmaceutical.(3) Enlargement. Using pilot equipments and optimized conditions, products of small particle size(about 200 nm), uniform particle size distribution and high drug loading have been received.(4) Characterized of nanocrystal with drugs. Particle size and distribution(PDI) of samples were about 200 nm. Drug loading and encapsulation efficiency was measured by UV spectrophotometer(UV) and high performance liquid chromatography(HPLC). The drug loading capacity of itraconazole was amounted to 85.6% ± 0.6% and the drug loading capacity of somcl-9112 and curcumin was 11.40% ± 0.57%, 15.63% ± 2.57% separately. Different protein had different drug loading capability. Using scanning electron microscopy(SEM), transmission electron microscopy(TEM) to characterize the appearance, the results were spherical or ellipsoidal particles with uniform particle size. Using X-ray diffraction(XRD) and differential scanning calorimetry(DSC) to characterize the form of crystalline, the resuls were amorphous which may have better dissolution behavior and bioavailability. Oral curcumin nanocrystal system was only completed to the drug loading capacity due to the lack of time.(5) In vitro dissolution and pharmacokinetic experiments. According to the Chinese Pharmacopoeia 2010 edition, in vitro dissolution experiments showed that protein-drug nanocrystal systems could significantly improve drug solubility and dissolution rate. Pharmacokinetic experiments showed that the bioavailability of drug was improve. The AUC for each protein(purified casein, succinylated casein, whey protein, ?-lactalbumin, ?-lactoglobulin, ?-lactoglobulin+10% alb) loaded itraconazole group were 1.7 times, 3 times, 3.7 times, 3.4 times, 3.2 times and 3.2 times of Sporanox group. The AUC of whey protein loaded somcl-9112 group was 2.37 times of somcl-9112 group. Concentrations of curcumin dissolved in water was increased to the 291 times, 378 times, 402 times of original.In this study, we use proteins as oral nanocrystal stabilizers which are safe and effective, and proteins can also be modified by succinic anhydride to enhance its carrier performance, to provide reference for increasing the solubility of poorly soluble drugs and also applying to other drugs or fields for the carrier system.