Encapsulation of Andrographolide in poly(lactide-co-glycolide) Nanoparticles: Formulation Optimization and in vitro Efficacy Studies.

Andrographolide is a potential chemopreventive and chemotherapeutic agent that suffers from poor aqueous solubility. Encapsulation in poly(lactide-co-glycolide) (PLGA) nanoparticles can overcome solubility issues and enable sustained release of the drug, resulting in improved therapeutic efficacy. In this study, andrographolide was encapsulated in PLGA nanoparticles via emulsion solvent evaporation technique. Effect of various formulation parameters including polymer composition, polymer molecular weight, polymer to drug ratio, surfactant concentration and the organic solvent used on nanoparticle properties were investigated. A selected formulation was used to determine the effect of encapsulation in nanoparticles on andrographolide's in vitro anticancer efficacy. Nanoparticles formulated using a polymer with 85:15 lactide to glycolide ratio and ethyl acetate as the organic solvent were found to be optimal based on average hydrodynamic particle size (135 ± 4 nm) and drug loading (2.6 ± 0.6%w/w). This formulation demonstrated sustained release of andrographolide over 48 h and demonstrated significantly greater in vitro anticancer efficacy compared to free drug in a metastatic breast cancer cell line. These results suggest that additional, more in-depth efficacy studies are warranted for the nanoparticle formulation of andrographolide.

Nanoformulated Eudragit lopinavir and preliminary release of its loaded suppositories.

The development of novel paediatrics formulations is critical towards achieving the UNAIDS 90-90-90 targets. According to the latest UNAIDS reports, the availability of antiretrovirals (ARVs) for children has increased significantly, from 49% in 2015 to 53% in 2017. However, this percentage is considerably lower than the 80% for pregnant women that are currently on treatment. Therefore, there is still an urgent need for an alternative child-friendly delivery system. Lopinavir (LPV) is a protease inhibitor first-line HIV treatment drugs but suffers from low aqueous solubility, bitter state, short half-life leading to a limited dissolution and variable bioavailability upon oral administration. This work focused on the fabrication and characterization of a delivery system entailing Eudragit RSPO-LPV nanoparticles loaded suppositories in two different bases to improve the bioavailability and overcome the problem encountered through oral administration emanating from poor solubility. The prepared nanoparticles by nanoprecipitation method were characterized and compounded into suppositories in fattibase and polyethylene glycol (PEG) bases using a melt fusion method. The suppositories were stored at 5 and 25 °C, and were sampled at 0, 4, 8, 12 weeks. The samples were assessed by particle size, entrapment efficiency (EE), zeta potential and polydispersity index (PDI) variations. The preliminary in vitro release studies were analysed by HPLC. The nanoparticles have an average particle size of 191 nm with spherical morphology, entrapment efficiency, polydispersity index and zeta potential of 79.0 ± 0.5%, 0.224, and 25.87 ± 0.41 mV respectively. The surface analysis of the nanoparticles with FTIR, SEM, PXRD and TGA indicated that the drug was truly encapsulated without any interaction. The in vitro release studies showed that a better release was observed in suppositories formulated with PEG than the fattibase by having higher drug concentration released. Hence, this rectal formulation might serve as an alternative for paediatric HIV treatment upon further investigation.

Formulation and Optimization of Gentamicin Hydrogel Infused with Tetracarpidium Conophorum Extract via a Central Composite Design for Topical Delivery.

OBJECTIVES: Response surface methodology coupled with statistically designed experiments has been found to be very useful in optimising multivariable processes. The aim of this study was to evaluate the influence of two independent variables, a ratio of permeation enhancers/antioxidants (transcutol and ethanolic extract of tetracarpidium conophorum EETC) and stirring rate, on the flux and permeation of gentamicin hydrogel. MATERIALS AND METHODS: A modification of free radical initial polymerization was used to formulate the gentamicin hydrogel. A 32 factorial CCD was then used to investigate the effect of independent variables of the permeation enhancer transcutol: EETC (X1), stirring speed (X2) via 14 formulation batches, which were evaluated for dependent variables flux (Y1) and amount of drug permeated after 12 hours (Y2) ex vivo. RESULTS: The results of ANOVA performed to determine the fit of the models revealed that the models were statistically significant (p<0.05) and did not show lack of fit (R2>0.80). The regression equation generated for flux was Y1=19.35 - 25.82X1 - 0.044X2 + 0.0097X1X2 + 11.86X21 and for cumulative permeation of gentamicin in 12 hours Y2=315.50 - 189.67X1 + 0.28X2 -1.29X1X2 + 123.55X21. The validity of the statistical models used for predicting flux and drug permeation was confirmed by conducting three confirmation experimental runs at the identified optimum conditions. The results showed that there was no significant difference between the experimental results and those predicted by the statistical models. CONCLUSION: The excellent correlation between the predicted and measured values shows the validity of statistical models (R2=0.95). An antioxidant and permeation enhancer has been used for the first time to investigate the influence on dependent variables. Optimization of gentamicin hydrogel using central composite statistical design is valid for the prediction of drug permeation and flux using variables in formulation.

Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels - A Strategy for Brain Cancer Treatments.

PURPOSE: The blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosuppression. METHODS: Mice were dosed with either intravenous lomustine Molecular Envelope Technology (MET) nanoparticles (13 mg kg(-1)) or ethanolic lomustine (6.5 mg kg(-1)) and tissues analysed. Efficacy was assessed in an orthotopic U-87 MG glioblastoma model, following intravenous MET lomustine (daily 13 mg kg(-1)) or ethanolic lomustine (daily 1.2 mg kg(-1) - the highest repeated dose possible). Myelosuppression and MET particle macrophage uptake were also investigated. RESULTS: The MET formulation resulted in modest brain targeting (brain/ bone AUC0-4h ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC0-4h ratios for MET and ethanolic lomustine = 0.24 and 0.15 respectively). The MET formulation significantly increased mice (U-87 MG tumours) survival times; with MET lomustine, ethanolic lomustine and untreated mean survival times of 33.2, 22.5 and 21.3 days respectively and there were no material treatment-related differences in blood and femoral cell counts. Macrophage uptake is slower for MET nanoparticles than for liposomes. CONCLUSIONS: Particulate drug formulations improved brain tumour therapy without major bone marrow toxicity.