Recent research and development of local anesthetic-loaded microspheres.

Local anesthetic drugs are widely used in postoperative analgesia, local nerve block in surgery, and in the therapy of chronic pain. Due to their short half-time, a single administration of local anesthetics merely maintains the nerve block for several hours, which cannot meet the long-term analgesia effect needed in clinical treatment. In order to break through this limitation of local anesthetics, research work regarding controlled drug release from microspheres has attracted broad and current interest. This review introduces the recent research and development in local anesthetic-loaded microspheres for future clinical applications, where for an efficient microsphere formulation, the most critical aspects are an optimum preparation method, a high loading efficiency, and an ideal release rate. This review first summarizes the recent preparation methods of local anesthetic-loaded microspheres, which includes emulsion-solvent evaporation, spray-drying, microfluidic droplets, and premix membrane emulsification technology. Next, strategies for increasing the loading efficiency of the drug in microspheres are reviewed based on the solidification conditions, polymer properties, microsphere formulation, including the external water phase, pH, and polymer concentration. Finally, the effects of the preparation conditions, material characteristics, particle characteristics, and hydrogel/microsphere composite systems on the controlled release behavior are summarized.

Thermal-sensitive hydrogels as nasal vaccine delivery systems.

The National Key Laboratory of Biochemical Engineering established in 1995 is affiliated with the Institute of Process Engineering, Chinese Academy of Sciences (CAS), and located in Zhong-guan-cun (Beijing, China). The National Key Laboratory of Biochemical Engineering is working towards developments in the fields of bio-reaction, bioseparation and bio-formulation, by chemical and material methods. Over the last 5 years, approximately 200 scientists and students have worked at the laboratory, and published over 400 articles. Numerous universities, companies and institutes have established cooperative relationships with this laboratory, and over 70 cooperative research programs with other researchers have been conducted in the past few years.

Novel thermal-sensitive hydrogel enhances both humoral and cell-mediated immune responses by intranasal vaccine delivery.

A novel thermal sensitive hydrogel was formulated with N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC) and α, ß-glycerophosphate (α, ß-GP). A serial of hydrogels containing different amount of GP and HTCC with diverse quarternize degree (QD, 41%, 59%, 79.5%, and 99%) were prepared and characterized by rheological method. The hydrogel was subsequently evaluated for intranasal vaccine delivery with adenovirus based Zaire Ebola virus glycoprotein antigen (Ad-GPZ). Results showed that moderate quarternized HTCC (60% and 79.5%) hydrogel/antigen formulations induced highest IgG, IgG1, and IgG2a antibody titers in serum, as well as mucosal IgA responses in lung wash, which may attributed to the prolonged antigen residence time due to the thermal-sensitivity of this hydrogel. Furthermore, CD8(+) splenocytes for IFN-γ positive cell assay and the release profile of Th1/Th2 type cytokines (IFN-γ, IL-2, IL-10, and IL-4) showed that hydrogel/Ad-GPZ generated an overwhelmingly enhanced Th1 biased cellular immune response. In addition, this hydrogel displayed low toxicity to nasal tissue and epithelial cells even by frequently intranasal dosing of hydrogel. All these results strongly supported this hydrogel as a safe and effective delivery system for nasal immunization.

Thermal-sensitive hydrogel as adjuvant-free vaccine delivery system for H5N1 intranasal immunization.

For H5N1 influenza immunization, we developed a thermal-sensitive hydrogel as intranasal vaccine delivery system, which was formulated with N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC) and α, ß-glycerophosphate (α, ß-GP). The flowing solution of HTCC/GP under room temperature could gelate rapidly at body temperature, which significantly prolonged the H5N1 split antigen residence time in nasal cavity. This system also enhanced the transepithelial transport via the paracellular routes due to the disorganization of ZO-1 protein in nasal epithelial tissue. In comparison to naked H5N1 split antigen and MF59 adjuvanted antigen, as designed hydrogel/H5N1 vaccine induced greater antigen-specific systemic immune responses and mucosal IgA immunity without adjuvants. Furthermore, a boosted cellular and humoral response was also obtained by examination of IFN-γ and IL-4 cytokines, respectively. In addition, hydrogel based formulation promoted the antigen-specific CD8(+) T cell immune memory as determined by the proportion of central and effector memory CD8(+) T cells in nasal associated lymphoid tissue (NALT). These results demonstrate that the HTCC hydrogel has potential as an adjuvant-free platform for H5N1 split antigen intranasal vaccination.