Developing novel mucoadhesive chitosan based formulations for drug delivery to the urinary bladder

My PhD project aims to develop novel chitosan derivatives (with superior mucoadhesiveness) for transmucosal application. The intravesical route was chosen as the exemplar transmucosal mode of drug delivery due to the limited therapeutic efficiency of conventional bladder cancer formulations. Drug carriers with improved mucoadhesive properties may prolong drug residence in the bladder. First, three chitosan grades were used to prepare chitosan/β-glycerophosphate in situ gelling mixtures and from these grades, the high molecular weight graded chitosan (HCHI) was chosen for chemical derivatisation based on its superior gelation, mucoadhesive and drug release potential. HCHI was conjugated with varying amounts of methacrylate or phenylboronate groups in order to evaluate the influence of the type and amount of conjugated hydrophobic pendant group on their physicochemical and mucoadhesive properties. The boronated and methacrylated chitosans were characterised using 1H NMR and FT- IR. There was good correlation in the extent of hydrophobic modification for methacrylated and boronated chitosans using 1H NMR and ninhydrin test. Methacrylated and boronated chitosan exhibited comparable resistance to pH influence on their solubility. The degree of methacrylate or boronate conjugation had a significant influence on the mucoadhesiveness of the drug carriers studied using a urine flow-through technique/fluorescent microscopy as well as a texture analyser, on porcine bladder in vitro. Boronate groups conferred superior mucoadhesive behaviour on chitosan relative to methacrylate groups. Methacrylated chitosan displayed a similar safety profile to the parent chitosan based on MTT assay on UMUC3 bladder cancer cells. The biocompatibility studies of boronated chitosan will be carried out in future studies using bladder cell lines despite the fact that several in vitro and in vivo studies have established the safety of phenylboronic molecules. Methacrylation and boronation of chitosan has been identified as efficient strategies to generate more mucoadhesive drug carriers which could prolong drug residence time in the bladder thereby improving therapeutic outcomes of bladder cancer patients. These novel polymers were easily synthesised requiring minimal equipment suitable for industrial scale-up. These excipients could be used to formulate affordable transmucosal dosage forms with superior mucoadhesiveness for a variety of biomedical applications

In situ gelling drug delivery systems for topical drug delivery

In situ gelling formulations are drug delivery systems which typically exist in a sol form at room temperature and change into gel state after application to the body in response to various stimuli such as changes in temperature, pH and ionic composition. Their biomedical application can further be improved by incorporating drug nanoparticles into in situ gelling systems in order to prolong drug release, reduce dosing frequency and improve therapeutic outcomes of patients, developing highly functional but challenging dosage forms. The composition of in situ gelling formulations influence factors relating to performance such as their syringeability, rheology, drug release profile and drug bioavailability at target sites, amongst other factors. The inclusion of mucoadhesive polymeric constituents into in situ gelling formulations has also been explored to ensure that the therapeutic agents are retained at target site for extended period of time. This review article will discuss traditional techniques (water bath-based vial inversion and viscometry) as well as advanced methodology (rheometry, differential scanning calorimetry, Small Angle Neutron Scattering, Small Angle X-ray Scattering, etc.) for evaluating in situ gel forming systems for topical drug delivery. The clinical properties of in situ gelling systems that have been studied for potential biomedical applications over the last ten years will be reviewed to highlight current knowledge in the performance of these systems. Formulation issues that have slowed the translation of some promising drug formulations from the research laboratory to the clinic will also be detailed

In situ gelling drug delivery systems for topical drug delivery

© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY licence. https://creativecommons.org/licenses/by/4.0/In situ gelling formulations are drug delivery systems which typically exist in a liquid form at room temperature and change into gel state after application to the body in response to various stimuli such as changes in temperature, pH and ionic composition. Their biomedical application can further be improved by incorporating drug nanoparticles into in situ gelling systems in order to prolong drug release, reduce dosing frequency and improve therapeutic outcomes of patients, developing highly functional but challenging dosage forms. The composition of in situ gelling formulations influence factors relating to performance such as their syringeability, rheology, drug release profile and drug bioavailability at target sites, amongst other factors. The inclusion of mucoadhesive polymeric constituents into in situ gelling formulations has also been explored to ensure that the therapeutic agents are retained at target site for extended period of time. This review article will discuss traditional techniques (water bath-based vial inversion and viscometry) as well as advanced methodology (rheometry, differential scanning calorimetry, Small Angle Neutron Scattering, Small Angle X-ray Scattering, etc.) for evaluating in situ gel forming systems for topical drug delivery. The clinical properties of in situ gelling systems that have been studied for potential biomedical applications over the last ten years will be reviewed to highlight current knowledge in the performance of these systems. Formulation issues that have slowed the translation of some promising drug formulations from the research laboratory to the clinic will also be detailed.Peer reviewe

Chitosan/β-glycerophosphate in situ gelling mucoadhesive systems for intravesical delivery of mitomycin-C

The development of mucoadhesive in situ gelling formulations for intravesical application may improve the therapeutic outcomes of bladder cancer patients. In this work, chitosan/β-glycerophosphate (CHIGP) thermosensitive formulations have been prepared using three different chitosan grades (62, 124 and 370 kDa). Their ability to form in situ gelling systems triggered by changes in temperature upon administration to urinary bladder were evaluated using vial inversion and rheological methods. Texture analysis was used to study their mucoadhesive properties as well as syringeability through the urethral catheter. The retention of CHIGP formulations, with fluorescein sodium as the model drug, was studied on porcine urinary bladder mucosa ex vivo using the flow-through technique and fluorescent microscopy. CHIGP formulations containing mitomycin-C were prepared and drug release was studied using in vitro dialysis method. It was established that the molecular weight of chitosan influenced the thermogelling, mucoadhesive and drug release behaviour of the in situ gelling delivery systems. Formulations prepared from chitosan with greatest molecular weight (370 kDa) were found to be the most promising for intravesical application due to their superior gelling properties and in vitro retention in the bladder

Synthesis and evaluation of boronated chitosan as a mucoadhesive polymer for intravesical drug delivery

This work reports the synthesis of boronated chitosan by reacting it with 4-carboxyphenylboronic acid to improve its mucoadhesive properties. Three products with differing extent of boronate conjugation were synthesised and characterised using 1H NMR, FT-IR and UV-Vis spectroscopy and the potential of these polymers to extend the residence time of loaded model drug in the bladder was investigated. 1H NMR and ninhydrin test were used to evaluate the extent of chitosan modification. Mucoadhesive properties were evaluated using ex vivo flow-through technique on porcine bladder mucosal tissue combined with fluorescent microscopy, where fluorescein sodium was used as a model drug. The mucoadhesive properties of these polymers on porcine bladder mucosa were also studied using tensile test. There was good correlation in the mucoadhesive profiles of the polymers using the flow through and tensile techniques. The degree of chitosan modification had a remarkable influence on their mucoadhesive behaviour and greater mucoadhesion was observed with increased degree of boronation. These chitosan derivatives have the potential as intravesical drug delivery systems to improve bladder therapy

Methacrylated chitosan as a polymer with enhanced mucoadhesive properties for transmucosal drug delivery

Chitosan is a cationic polysaccharide that exhibits mucoadhesive properties which allow it to adhere to mucosal tissues. In this work, we explored chemical modification of chitosan through its reaction with methacrylic anhydride to synthesise methacrylated derivative with the aim to improve its mucoadhesive properties. The reaction products were characterised using 1H NMR, FTIR and UV–Vis spectroscopy. 1H NMR and ninhydrin test were used to quantify the degree of methacrylation of chitosan. Turbidimetric analysis of the effect of pH on aqueous solubility of the polymers revealed that the highly methacrylated derivative remained turbid and its turbidity did not change from pH 3 to 9. However, solutions of native chitosan and its derivative with low methacrylation remained transparent at pH 6.5 and exhibited a rapid increase in turbidity at pH > 6.5. The mucoadhesive properties of chitosan and its methacrylated derivatives were evaluated using flow-through method combined with fluorescent microscopy with fluorescein sodium as a model drug. The retention of these polymers was evaluated on porcine bladder mucosa in vitro. The methacrylated derivatives exhibited greater ability to retain fluorescein sodium on the bladder mucosa compared to the parent chitosan. Toxicological studies using MTT assay with UMUC3 bladder cells show no significant differences in toxicity between chitosan and its methacrylated derivatives suggesting good biocompatibility of these novel mucoadhesive polymers

APOE E4 is associated with impaired self-declared cognition but not disease risk or age of onset in Nigerians with Parkinson's disease

The relationship between APOE polymorphisms and Parkinson's disease (PD) in black Africans has not been previously investigated. We evaluated the association between APOE polymorphic variability and self-declared cognition in 1100 Nigerians with PD and 1097 age-matched healthy controls. Cognition in PD was assessed using the single item cognition question (item 1.1) of the MDS-UPDRS. APOE genotype and allele frequencies did not differ between PD and controls (p > 0.05). No allelic or genotypic association was observed between APOE and age at onset of PD. In PD, APOE ε4/ε4 conferred a two-fold risk of cognitive impairment compared to one or no ε4 (HR: 2.09 (95% CI: 1.13-3.89; p = 0.02)), while APOE ε2 was associated with modest protection against cognitive impairment (HR: 0.41 (95% CI 0.19-0.99, p = 0.02)). Of 773 PD with motor phenotype and APOE characterized, tremor-dominant (TD) phenotype predominated significantly in ε2 carriers (87/135, 64.4%) compared to 22.2% in persons with postural instability/gait difficulty (PIGD) (30/135) and 13.3% in indeterminate (ID) (18/135, 13.3%) (p = 0.037). Although the frequency of the TD phenotype was highest in homozygous ε2 carriers (85.7%), the distribution of motor phenotypes across the six genotypes did not differ significantly (p = 0.18). Altogether, our findings support previous studies in other ethnicities, implying a role for APOE ε4 and ε2 as risk and protective factors, respectively, for cognitive impairment in PD

Advances in intravesical drug delivery systems to treat bladder cancer

Chemotherapeutic agents administered intravesically to treat bladder cancer have limited efficacy due to periodic dilution and wash-out during urine formation and elimination. This review describes the pathophysiology, prevalence and staging of bladder cancer, and discusses several formulation strategies used to improve drug residence within the bladder. These include the use of amphiphilic copolymers, mucoadhesive formulations, hydrogels, floating systems, and liposomes. Various in vitro and in vivo models recently employed for intravesical drug delivery studies are discussed. Some of the challenges that have prevented the clinical use of some promising formulations are identified

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission