Development of novel delivery systems for nose-to-brain drug delivery

The blood brain barrier (BBB) poses a significant hurdle to brain drug delivery. However, the location of the olfactory mucosa, within the nasal cavity, is a viable target site for direct nose-to-brain (N2B) delivery, thereby bypassing the BBB. To exploit this target site innovative nasal formulations are required for targeting and increasing residency within the olfactory mucosa. We developed and characterised three formulation systems for N2B delivery, (i) thermoresponsive mucoadhesion nasal gels sprays; (ii) mesoporous silica nanoparticles and (iii) nasal pMDI devices. We developed an optimal mucoadhesive formulation system incorporating amantadine as a model, water-soluble anti-Parkinson’s drug using carboxymethy cellulose and chitosan as mucoadhesives. Formulations demonstrated droplet sizes of < 130mm and stability over 8-weeks when stored at refrigeration conditions with no significant cellular toxicity against olfactory bulb (OBGF400) and nasal epithelial (RPMI 2650) cells. Mesoporous silica nanoparticles (MSNP) were prepared (~220nm) and demonstrated cellular uptake into OBGF400 within 2-hours of incubation with minimal toxicity. MSNP were loaded with two novel phytochemicals known to possess CNS activity, curcumin and chrysin, with loading efficiencies of ~12% confirmed through TGA, DSC and HPLC-UV analysis. Furthermore, a pH dependant release profile was identified with curcumin with greater release at nasal cavity pH 5.5 compared to pH 7.4. Furthermore, successful incorporation of MSNP into nasal gels was demonstrated through rheological studies with a decrease in Tsol-gel. A pilot study was conducted to assess the feasibility of modified existing pulmonary pMDI to deliver diazepam intranasally, targeting the olfactory mucosa. Diazepam was formulated with HFA134a and using ethanol as a co-solvent, and demonstrated stability in formulation over 3 months. Deposition studies within a nasal cast model demonstrated 5-6% deposition onto the olfactory mucosa under optimal administration conditions in the absence of any nozzle attachments. Our studies have provided a basis for the development to innovative intranasal formulation systems potentially capable of targeting the olfactory mucosa for both water soluble and poorly soluble drugs

Development and Evaluation of a Novel Intranasal Spray for the Delivery of Amantadine

The aim of this study was to develop and characterise an intranasal delivery system for amantadine (AMT). Optimal formulations (F) consisted of a thermosensitive polymer Pluronic® 127 (P127) and either carboxy methyl cellulose (CMC) or chitosan (CS) which demonstrated gel-transition at nasal cavity temperatures (34 °C ± 1 °C). Rheologically, the loss tangent (Tan δ) confirmed a three-stage gelation phenomena at 34 °C ± 1 °C and non-Newtonian behaviour. Storage of FCMC and FCS at 4 °C for 8 weeks resulted in repeatable release profiles at 34 °C when sampled, with a Fickian mechanism earlier on but moving towards anomalous transport by week 8. Polymers (P127, CMC and CS) demonstrated no significant cellular toxicity to human nasal epithelial cells up to 4 mg/mL and up to 1 mM for AMT (IC50: 4.5 mM ± 0.05 mM). FCMC and FCS demonstrated slower release across an in-vitro human nasal airway model (43-44 % vs 79 % ± 4.58 % for AMT). Using a human nasal cast model, deposition into the olfactory regions (potential nose-to-brain) was demonstrated upon nozzle insertion (5 mm) whereas tilting of the head forward (15°) resulted in greater deposition in the bulk of the nasal cavity

Phytochemical-loaded mesoporous silica nanoparticles for nose-to-brain olfactory drug delivery

Central nervous system (CNS) drug delivery is often hampered due to the insidious nature of the blood-brain barrier (BBB). Nose-to-brain delivery via olfactory pathways have become a target of attention for drug delivery due to bypassing of the BBB. The antioxidant properties of phytochemicals make them promising as CNS active agents but possess poor water solubility and limited BBB penetration. The primary aim of this study was the development of mesoporous silica nanoparticles (MSNs) loaded with the poorly water-soluble phytochemicals curcumin and chrysin which could be utilised for nose-to-brain delivery. We formulated spherical MSNP using a templating approach resulting in ∼220nm particles with a high surface porosity. Curcumin and chrysin were successfully loaded into MSNP and confirmed through Fourier transformation infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and HPLC approaches with a loading of 11-14% for curcumin and chrysin. Release was pH dependant with curcumin demonstrating increased chemical stability at a lower pH (5.5) with a release of 53.2%±2.2% over 24h and 9.4±0.6% for chrysin. MSNP were demonstrated to be non-toxic to olfactory neuroblastoma cells OBGF400, with chrysin (100μM) demonstrating a decrease in cell viability to 58.2±8.5% and curcumin an IC50 of 33±0.18μM. Furthermore confocal microscopy demonstrated nanoparticles of <500nm were able to accumulate within cells with FITC-loaded MSNP showing membrane localised and cytoplasmic accumulation following a 2h incubation. MSNP are useful carriers for poorly soluble phytochemicals and provide a novel vehicle to target and deliver drugs into the CNS and bypass the BBB through olfactory drug delivery

Overcoming Parkinson’s disease: direct nose-to-brain delivery of amantadine

Treatments for Parkinson’s disease face significant challenges in delivery to the due to the presence of blood brain barrier (BBB). The aim of this study was to develop and characterise an in-situ thermoresponsive polymer based gel system for possible exploitation of the intranasal olfactory route where the BBB is absent. Reaching the olfactory region in the nasal cavity and mucociliary clearance are the main hurdles from formulation point of view. Thermo-sensitive and pH sensitive polymers seem to be the answer to these problems. Formulation made with these polymers along with mucoadhesives will be liquid at room temperature and will turn into a viscous gel when comes in contact with the body either due to change in pH or temperature. We have successfully prepared the gels using cold method using amantadine, with Pluronic F127 as a thermoreversible polymer and carboxymethylcelluose (CMS) as a mucoadhesive polymer. Rheological characterisation confirmed the sol-to-gel phenomenon at desired temperatures. CMC increased the gelation temperature with increase in concentration, whereas amantadine lowered the gelation temperature with increase in concentration. After preliminary studies, 16 % of Pluronic F127 found to be a suitable concentration for the formulation to change from sol-to-gel at ambient nasal temperatures. Molecular, gene expression and drug transport studies using the nasal epithelial cell lines RPMI 2650 are also under investigation along with the development of an in-vitro olfactory-epithelial cell culture model to study axonal transport. Unlike the animal studies this model will be faster to use, efficient and also better representation of human olfactory system

Phytochemical-loaded mesoporous silica nanoparticles for nose-to-brain olfactory drug delivery

Central nervous system (CNS) drug delivery is often hampered due to the insidious nature of the blood-brain barrier (BBB). Nose-to-brain delivery via olfactory pathways have become a target of attention for drug delivery due to bypassing of the BBB. The antioxidant properties of phytochemicals make them promising as CNS active agents but possess poor water solubility and limited BBB penetration. The primary aim of this study was the development of mesoporous silica nanoparticles (MSNs) loaded with the poorly water-soluble phytochemicals curcumin and chrysin which could be utilised for nose-to-brain delivery. We formulated spherical MSNP using a templating approach resulting in ∼220nm particles with a high surface porosity. Curcumin and chrysin were successfully loaded into MSNP and confirmed through Fourier transformation infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and HPLC approaches with a loading of 11-14% for curcumin and chrysin. Release was pH dependant with curcumin demonstrating increased chemical stability at a lower pH (5.5) with a release of 53.2%±2.2% over 24h and 9.4±0.6% for chrysin. MSNP were demonstrated to be non-toxic to olfactory neuroblastoma cells OBGF400, with chrysin (100μM) demonstrating a decrease in cell viability to 58.2±8.5% and curcumin an IC50 of 33±0.18μM. Furthermore confocal microscopy demonstrated nanoparticles of <500nm were able to accumulate within cells with FITC-loaded MSNP showing membrane localised and cytoplasmic accumulation following a 2h incubation. MSNP are useful carriers for poorly soluble phytochemicals and provide a novel vehicle to target and deliver drugs into the CNS and bypass the BBB through olfactory drug delivery