A Holistic Approach for Fill volume Variability Evaluation and Control with Statistical Tool.

Vial and syringe filling by peristaltic pump has been widely implemented by contract manufacturing organizations and biopharmaceutical companies. Fill volume is commonly considered as critical quality attribute related in aseptic filling process and the variation needs to be well controlled to guarantee the safety, efficacy and consistency of drug products. However, the criteria for justifying the filling variation and underlying mechanisms that affect the variability are not fully revealed quantitatively in the literatures. This study selected filling accuracy, filling process capability and filling precision as three criteria for evaluating the filling process performance with four statistical indexes: Relative Error Mean, Critical Control Limit (Cpk ≥ 1.33), Relative Standard Deviation and Relative Moving Range Mean. The impact of liquid properties, pump tubing sizes and pump settings on above indexes were investigated using a bench-top system with a peristatic pump and a high-precision balance. The results showed that the viscosity, target fill volume, pump tubing size, pump speed, acceleration/deceleration rate and suck-back had statistical significance on the fill volume variability. Definitive Screening Design was further applied to clarify and visualize the priorities and interaction impact of above factors on fill volume variability. Stepwise approach for fill volume variability optimization and control based on predictive models was established and verified for drug product solution with viscosity between 1-23 cp and target fill volume between 0.2-2.0 mL.

NIR Activated Upper Critical Solution Temperature Polymeric Micelles for Trimodal Combinational Cancer Therapy.

The balance between drug efficiency and its side effects on normal tissues is still a challenging problem to be solved in current cancer therapies. Among different strategies, cancer therapeutic methods based on nanomedicine delivery systems have received extensive attention due to their unique advantages such as improved circulation and reduced toxicity of drugs in the body. Herein, we constructed dual-responsive polymeric micelles DOX&ALS@MFM based on an upper critical solution temperature (UCST) polymer to simultaneously combine chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT). Amphiphilic block copolymer P(AAm-co-AN)-b-PEI-ss-PEG-FA with a critical point of 42 °C was able to self-assemble into polymeric micelles under physiological conditions, which further encapsulated anticancer drug doxorubicin (DOX) and photosensitizer ALS to obtain drug-loaded micelles DOX&ALS@MFM. Micelles aggregated at tumor sites due to folate targeting and an enhanced permeability retention (EPR) effect. After that, the high intracellular concentration of glutathione (GSH) and near-infrared (NIR) light prompted disassembly of the polymer to release DOX and ALS. ALS not only plays a role in PTT but also produces singlet oxygen, therefore killing tumor cells by PDT. Both in vitro and in vivo studies demonstrated the photothermal conversion and reactive oxygen species generation ability of DOX&ALS@MFM micelles, at the same time as the excellent inhibitory effect on tumor growth with NIR light irradiation. Thus, our research substantiated a new strategy for the biomedical application of UCST polymers in the cited triple modal tumor therapy.

On-demand transdermal insulin delivery system for type 1 diabetes therapy with no hypoglycemia risks.

Diabetes is a metabolic disease that is affecting an ever-increasing number of people worldwide, resulting in increased burdens on healthcare systems and societies. Constant monitoring of blood glucose levels is required to prevent serious or even deadly complications. One major challenge of diabetes management is the simple and timely administration of insulin to facilitate consistent blood glucose regulation and reduce the incidence of hypoglycemia. With this research, we construct an insulin delivery system, the delivery system is comprised of phenylboronic acid based fluorescent probes, which is used as glucose responsive linkers, mesoporous silica nanoparticles providing an insulin reservoir, and zinc oxide nanoparticles used as gate keepers. The system with glucose sensitive responsive linker exhibits controlled release of insulin under high glucose concentrations, providing prolonged blood glucose regulation and no risks of hypoglycemia. Furthermore, the system is combined with a hyaluronic-acid based microneedle patch, which exhibit efficient skin penetration for transdermal delivery. With our system, the nanoparticles provide outstanding in vivo glucose regulation when administrated by subcutaneous injection or via transdermal microneedle patch. We anticipate that our biocompatible smart glucose responsive microneedle patch (SGRM patch) will facilitate the development of clinically useful systems.

Dually responsive mesoporous silica nanoparticles regulated by upper critical solution temperature polymers for intracellular drug delivery.

We synthesized a new type of upper critical solution temperature (UCST) thermally responsive polymers (TRPs) with varying responsive temperatures (cloud points). We then grafted one of the TRPs with a cloud point of 42°C on the surface of mesoporous silica nanoparticles (MSN) using disulfide bonds to achieve a novel, dual responsive release system. With this system, the cargo release profiles are responsive to both temperature and reducing agents. When loaded with doxorubicin hydrochloride (DOX), the system could deliver DOX into breast cancer cells (SK-BR-3) in a controlled fashion and present high toxicity.

Ammonium salt modified mesoporous silica nanoparticles for dual intracellular-responsive gene delivery.

Effective gene delivery system plays an importmant role in the gene therapy. Mesoporous silica nanoparticle (MSN) has become one potential gene delivery vector because of its high stability, good biodegradability and low cytotoxicity. Herein, MSN-based dual intracellular responsive gene delivery system CMSN-A was designed and fabricated. Short chain ammonium group, which is modified with disulfide bond and amide bond simultaneously, is facilely grafted onto the mesoporous silica nanoparticles. As-synthesized CMSN-A is endowed with small size (80-110nm), large conical pores (15-23nm), and moderate Zeta potential (+25±2mV), which behaves high gene loading capacity, good stability and effectively gene transfection. Moreover, CMSN-A exhibits dual micro-environment responsive (lower pH, more reducing substances) due to the redox-sensitive disulfide bond and pH-sensitive amide bond in the short chain ammonium group. The cellular uptake study indicates that CMSN-A could transfer both plasmid DNA (pDNA) and siRNA into different kinds of tumour cells, which demonstrate the promising potential of CMSN-A as effective and safe gene-delivery vectors.