Food Protein Stabilized Oral Nano - Drug Delivery System And Its "solidification"

Oral delivery of poorly water-souble drugs remains to be one of the most significant problems in the pharmaceutical field. Lower water solubility not only results in poor absorption and bioavailability, but also leads to extensive inter-individual variation in pharmacodynamics and efficacy/dose disproportion, which has become a key factor limiting their development. Nanoscale colloid drug delivery systems have great potential for enhancing the bioavailability of the poorly water-soluble drugs, owing to enhanced dissolution rate, improved bioavailability, proportionality and increased patient compliance via reduction of drug exposure. However, to stabilize the nanoscaled drug delivery systems, especially nanoemulsions, a large amount of surfactant (20to30%as of the oil phase, wt%) must be used, which hinders its therapeutic application due to toxicological concerns during long-term treatment. Moreover, the stability of nanoparticles in aqueous phase is poor, due to hydrolytic/oxidative degradation, particle growth, aggregation/agglomeration, change of crystallinity state and sedimentation/creamin. Solidification of the nanoparticles is an ideal strategy to address the problems, achieving long-term storage stability. Thus, new materials, possessing excellent stabilization effect and biocompatibility, need to be explored for the nanoscaled drug delivery systems. Hence, our present aim was to (1) construct the nanoscaled drug delivery systems (nanoemulsions, nanocapsules and nanocrystals) by utilizing three biocompatible food proteins (SPI, WPI and (3-LG) as stabilizers, and (2) then solidify the food protein-stabilized nanoscaled drug delivery systems to achieve long-term storage stability.Three food protein-stabilized nanoemulsions were prepared using technologies of a combination of mechanical mixing and high-pressure homogenization. The nanoemulsions were characterized with respect to particle size, zeta-potential, morphology and centrifugal stability. A comparative study between the food proteins and traditional emulsifiers in term of emulsification capacity and toxicity was performed. Specifically, a model poorly water-soluble drug, fenofibrate, was loaded into O/W nanoemulsions, and then in vitro release and pharmacokinetics in rats were evaluated. The nanoemulsions have particle size of about200nm with log-normal distribution. As emulsifiers, the proteins, WPI, SPI and β-LG, have better emulsifying capacity and biocompatibility than traditional emulsifiers. The particle size, stability and zeta-potential were affected dramatically by protein concentration, pH and homogenization pressure and number of cycles. The food proteins-stabilized nanoemulsion system with good biocompatibility allowed better and more rapid absorption of lipophilic drugs. It is concluded that by using the proteins as a surfactants, the development of biocompatible and biodegradable nanoemulsion systems can be achieved, and the proteins are viable replacements for traditional surfactants.A novel biocompatible shell-crosslinked nanocapsule system was developed based on nanoemulsion templates with biocompatible biopolymers (SPI/WPI/β-LG) as stabilizers. The rationale of our approach is to make the cross-linkers (Ca2+) bind to the biopolymers at the O/W interface, achieving shell cross-linking. The nanocapsules were prepared using a combination of mechanical mixing and high-pressure homogenization, with the nanoemulsion templates and cross-linked nanocapsules formed simultaneously. The effect of pH and cross-linker concentration on the cross-linking procedure was evaluated. The mechanisms of shell cross-linking of nanocapsules was also assessed. The cross-linked nanocapsules show significantly enhanced resistance toward dissociation by sodium dodecyl sulfate, which was better than that of noncross-linked nanocapsules. Cross-linking did not affect the biocompatibility of the system. The nanocapsules possessed excellent drug-loading capacity and encapsulation efficiency, which were not affected by the cross-linking process. In summary, we develop a new biocompatible shell-crosslinked nanocapsule system based on nanoemulsion templates stabilized by a class of biopolymers. The one-step preparative process is simple, and can be easily scaled up. A poorly water-soluble active compound, fenofibrate, was utilized as a model drug.Solidification of the shell cross-linked nanocapsules was performed by freeze-frying and fluid bed coating technology. The freeze-fried nanocapsules was prepared by freeze-drying the nanocapsule aqueous suspension directly, avoiding use of cryoprotectants; whereas the solid nanocapsules pellets were produced by layering the nanocapsule suspensions onto the nonpareil pellets with a fluid-bed coater, in which polyvinyl pyrrolidone was selected as a film-coating material. The redispersion of solid nanocapsules, in term of particle size, size distribution and morphology, was evaluated. The assessment of the physical state of the drug in solid nanocapsules was also performed. The solid nanocapsules were readily redispersed in water with well reserved particle size and morphology. The drug encapsulated in oil cores of nanocapsules did not leak during the solidification process, as detected by the DSC and PXRD experiment. It is concluded that the shell cross-linked nanocapsules formulated from nanoemulsion templates based on a class of biopolymers can be transferred into solid nanoparticles by freeze-frying or fluid-bed coating technology, making it potentially suitable for improving the long-term storage stability.We used precipitation-ultrasonication method to prepare the protein-stabilized indomethacin nanosuspensions, precipitated by mixing organic drug solution with water containing denatured protein. The effects of process parameters, protein concentration, drug concentration in organic phase, and pH values of aqueous solution on particle size were evaluated. After precipitation-ultrasonication, the protein can absorb onto the surface of drug particles which was based on the interactions between hydrophobic areas of protein and drug particles. TEM and SEM photographs of the nanosuspensions revealed a needle-like morphology with particle diameters about200to600nm. A significant smaller particle size of denatured SPI-, WPI-and (3-LG-nanosuspensions was observed when compared to that of common stabilizers, suggesting a more profound stabilization effect. An enhanced stabilization effect was observed when the proteins were subjected to a heat denatured process. The strong binding of the proteins to the drug particles, in turn, lead to conformation changes of the proteins, evidenced by fluorescence emission spectrum. A significant enhancement of drug dissolution was achieved as a result of particle size reduction to the nanoscale and amorphous drug particles. The stabilization mechanism of the food proteins for drug nanosuspensions is a combination of electrostatic repulsion and steric stabilization.Solidification of the food protein-stabilized nanosuspensions of indomethacin was carried out by freeze-frying and fluid bed coating technology. Nanosuspension containing5%(wt) trehalose, was rapidly frozen in liquid nitrogen, and then the frozen nansuspension was lyophilized; whereas the layered pellets were produced by coating the indomethacin nanosuspension onto the nonpareil pellets with a fluid-bed coater. Trehalose and SPI were used as protectants and polyvinyl pyrrolidone was used as film-coating materials. The redispersibility, drug dissolution, physical state of the drug, and morphology of the dried nanocrystals were evaluated. The conservation of a nanoparticle diameter size after the drying process indicated that the SPI/WPI/β-LG-stabilized nanosuspensions could be successfully converted into solid dosage form by freeze-frying and fluid bed coating technology. The redispersed nanocrystals stabilized by SPI, WPI or β-LG possessed similar morphology and particle size to that of original nanocrystals. Based on the results of DSC and PXRD, we concluded that the dried drug nanocrystals present as amorphous state, without being changed by the drying process.By using the three biocompatible food proteins as stabilizers, we successfully constructed a series of nanoscaled drug delivery systems including nanoemulsions, nanocapsules and nanocrystals. The food proteins have strong ability to stabilize the nanosystems, which can be transferred into solid dosage form by freeze-frying or fluid-bed coating technology, making it potentially suitable for improving the long-term storage stability and achieving industrial translation. The food proteins are promising materials for stabilizing the nanoscaled drug delivery systems.