Probucol-Ursodeoxycholic Acid Otic Formulations: Stability and In Vitro Assessments for Hearing Loss Treatment.

Targeted drug delivery is an ongoing aspect of scientific research that is expanding through the design of micro- and nanoparticles. In this paper, we focus on spray dried microparticles as carriers for a repurposed lipophilic antioxidant (probucol). We characterise the microparticles and quantify probucol prior to assessing cytotoxicity on both control and cisplatin treated hair cells (known as House Ear Institute-Organ of Corti 1; HEI-OC1). The addition of water-soluble polymers to 2% ß-cyclodextrin resulted in a stable probucol formulation. Ursodeoxycholic acid (UDCA) used as formulation excipient increases probucol miscibility and microparticle drug content. Formulation characterisations reveals spray drying results in spherical UDCA-drug microparticles with a mean size distribution of ∼5-12 µm. Probucol microparticles show stable short-term storage conditions accounting for only ∼10% loss over seven days. By mimicking cell culture conditions, both UDCA-probucol (67%) and probucol only (82%) microparticles show drug release in the initial two hours. Furthermore, probucol formulations with or without UDCA preserve cell viability and reduce cisplatin-induced oxidative stress. Mitochondrial bioenergetics results in lower basal respiration and non-mitochondrial respiration, with higher maximal respiration, spare capacity, ATP production and proton leak within cisplatin challenged UDCA-probucol groups. Overall, we present a facile method for incorporating lipophilic antioxidant carriers in polymer-based particles that are tolerated by HEI-OC1 cells and show stable drug release, sufficient in reducing cisplatin-induced reactive oxygen species accumulation.

Bile Acid Application in Cell-Targeting for Molecular Receptors in Relation to Hearing: A Comprehensive Review.

Bile acids play important roles in the human body, and changes in their pool can be used as markers for various liver pathologies. In addition to their functional effects in modulating inflammatory responses and cellular survivability, the unconjugated or conjugated, secondary, or primary nature of bile acids accounts for their various ligand effects. The common hydrophilic bile acids have been used successfully as local treatment to resolve drug-induced cell damage or to ameliorate hearing loss. From various literature references, bile acids show concentration and tissue-dependent effects. Some hydrophobic bile acids act as ligands modulating vitamin D receptors, muscarinic receptors, and calcium-activated potassium channels, important proteins in the inner ear system. Currently, there are limited resources investigating the therapeutic effects of bile acid on hearing loss and little to no information on detecting bile acids in the remote ear system, let alone baseline bile acid levels and their prevalence in healthy and disease conditions. This review presents both hydrophilic and hydrophobic human bile acids and their tissue-specific effects in modulating cellular integrity, thus considering the possible effects and extended therapeutic applicability of bile acids to the inner ear tissue.

Pharmaceutical characterization of probucol bile acid-lithocholic acid nanoparticles to prevent chronic hearing related and similar cellular oxidative stress pathologies.

Background: Sensorineural hearing loss has been associated with oxidative stress. However, an antioxidant that passes effectively through the ear remains elusive. Method: Probucol (PB)-based nanoparticles were formed using a spray-drying encapsulation technique, characterized and tested in vitro. Results: Uniform, spherical nanoparticles were produced. The addition of lithocholic acid to PB formulations did not affect drug content or production yield, but it did modify capsule size, surface tension, electrokinetic stability and drug release. Cell viability, bioenergetics and inflammatory profiles were improved when auditory cells were exposed to PB-based nanoparticles, which showed antioxidant properties (p < 0.05). Conclusion: PB-based nanoparticles can potentially protect the auditory cell line from oxidative stress and could be used in future in vivo studies as a potential new therapeutic agent for sensorineural hearing loss.

Oxidative stress is an imbalance of cellular processes in which the production of free radicals outweighs the cellular defense mechanism. The association of oxidative stress with the pathophysiology of sensorineural hearing loss (SHL) is well established. SHL development is associated with chronic damage in the structure of the inner ear or auditory nerve. Therefore, potent antioxidants such as probucol could be one way to prevent or treat SHL. However, due to its isolated position, SHL is challenging to treat, imposing a desperate need for refining existing therapeutic methods; one way to do this is by optimizing the formulation using nanoparticles. We aimed to design a novel, stable formulation of PB using polymers and excipients to develop nanoparticles and examine the efficiency of these formulations on the HEI-OC1 stress cell line. We found that the prepared nanoparticle is robust and stable and protects HEI-OC1 from cellular toxicity and oxidative stress. It could be a novel therapeutic agent to treat or prevent SHL.

The Effects of Primary Unconjugated Bile Acids on Nanoencapsulated Pharmaceutical Formulation of Hydrophilic Drugs: Pharmacological Implications.

INTRODUCTION: In a recent study, in our laboratory, primary unconjugated bile acids, commonly found in humans, chenodeoxycholic acid (CDCA), have been shown to improve stability of nanoencapsulated lipophilic drugs and improve their release profile after oral administration likely via electrokinetic stabilisation. Hence, this study aimed to examine the effects of CDCA on exerting similar effects on hydrophilic drugs. METHODS: Various CDCA-based formulations were produced for the orally administered hydrophilic drug, metformin. Analyses of these formulations included electrokinetic potentials, topography, drug and CDCA formulation contents, nano size distribution, heat-induced deformation and outer-core expansion indices, release profiles, shell-resistance ratio, and thermal and chemical indices. With the drug's main target being pancreatic beta-cells, the formulations' effects on cell viability, functions and inflammatory profiles were also investigated. RESULTS AND CONCLUSIONS: CDCA-based metformin formulations exhibited improved stability and release profiles via thermal, chemical and electrokinetic effects, which were formulation-dependent suggesting potential applications of CDCA in the oral targeted delivery of hydrophilic drugs.

Enhanced Bilosomal Properties Resulted in Optimum Pharmacological Effects by Increased Acidification Pathways.

INTRODUCTION: Recent studies in our laboratory have shown that some bile acids, such as chenodeoxycholic acid (CDCA), can exert cellular protective effects when encapsulated with viable ß-cells via anti-inflammatory and anti-oxidative stress mechanisms. However, to explore their full potential, formulating such bile acids (that are intrinsically lipophilic) can be challenging, particularly if larger doses are required for optimal pharmacological effects. One promising approach is the development of nano gels. Accordingly, this study aimed to examine biological effects of various concentrations of CDCA using various solubilising nano gel systems on encapsulated ß-cells. METHODS: Using our established cellular encapsulation system, the Ionic Gelation Vibrational Jet Flow technology, a wide range of CDCA ß-cell capsules were produced and examined for morphological, biological, and inflammatory profiles. RESULTS AND CONCLUSION: Capsules' morphology and topographic characteristics remained similar, regardless of CDCA or nano gel concentrations. The best pharmacological, anti-inflammatory, and cellular respiration, metabolism, and energy production effects were observed at high CDCA and nano gel concentrations, suggesting dose-dependent cellular protective and positive effects of CDCA when incorporated with high loading nano gel.

Applications of superparamagnetic iron oxide nanoparticles in drug and therapeutic delivery, and biotechnological advancements.

Superparamagnetic iron oxide nanoparticles (SPIONs) have unique properties with regard to biological and medical applications. SPIONs have been used in clinical settings although their safety of use remains unclear due to the great differences in their structure and in intra- and inter-patient absorption and response. This review addresses potential applications of SPIONs in vitro (formulations), ex vivo (in biological cells and tissues) and in vivo (preclinical animal models), as well as potential biomedical applications in the context of drug targeting, disease treatment and therapeutic efficacy, and safety studies.

Oral gavage of nano-encapsulated conjugated acrylic acid-bile acid formulation in type 1 diabetes altered pharmacological profile of bile acids, and improved glycaemia and suppressed inflammation.

BACKGROUND: Ursodeoxycholic acid (UDCA) is a secondary hydrophilic bile acid, metabolised in the gut, by microbiota. UDCA is currently prescribed for primary biliary cirrhosis, and of recently has shown ß-cell protective effects, which suggests potential antidiabetic effects. Thus, this study aimed to design targeted-delivery microcapsules for oral uptake of UDCA and test its effects in type 1 diabetes (T1D). METHODS: UDCA microcapsules were produced using alginate-NM30 matrix. Three equal groups of mice (6-7 mice per group) were gavaged daily UDCA powder, empty microcapsules and UDCA microcapsules for 7 days, then T1D was induced by alloxan injection and treatments continued until mice had to be euthanised due to weight loss > 10% or severe symptoms develop. Plasma, tissues, and faeces were collected and analysed for bile acids' concentrations. RESULTS: UDCA microcapsules brought about reduction in elevated blood glucose, reduced inflammation and altered concentrations of the primary bile acid chenodeoxycholic acid and the secondary bile acid lithocholic acid, without affecting survival rate of mice. CONCLUSION: The findings suggest that UDCA exerted direct protective effects on pancreatic ß-cells and this is likely to be associated with alterations of concentrations of primary and secondary bile acids in plasma and tissues. Three equal groups of mice were gavaged daily UDCA (ursodeoxycholic acid) powder, empty microcapsules and UDCA microcapsules for 7 days, then T1D was induced and treatments continued until mice had to be euthanised. UDCA microcapsules brought about reduction in elevated blood glucose, reduced inflammation and altered concentrations of the primary bile acid chenodeoxycholic acid and the secondary bile acid lithocholic acid, without affecting survival rate of mice. The findings suggest that UDCA exerted direct protective effects on pancreatic ß-cells and this is likely to be associated with alterations of concentrations of primary and secondary bile acids in plasma and tissues.

Histological effects of pharmacologically active human bile acid nano/micro-particles in Type-1 diabetes.

Aim: Gliclazide (G) is a drug prescribed for Type 2 diabetics, although recent studies suggest it has desirable effects in both types of diabetes, Type 1 diabetes and Type 2 diabetes. G has an inconsistent absorption due to poor formulation and bile acids (BAs) have shown significant promise in drug formulation optimization. Hence, the study aimed to examine G effects on histopathological, anti-inflammatory and antidiabetic effects when encapsulated with BAs. Materials & methods: Rats were randomized into eight groups, of which seven were made Type 1 diabetes and treated with various BA-based treatments. Tissue histopathology, inflammation and the bile acid profile were analyzed. Results & conclusion: G capsules showed no histological but the most anti-inflammatory effects, which suggest significant beneficial effects in diabetes treatment.

Formulation buoyancy of nanoencapsulated gliclazide using primary, conjugated and deconjugated bile acids.

Aim: Recent studies suggest potential applications of endogenously produced human bile acids as formulation-excipient and drug tissue permeation enhancers in Type 1 diabetes. We aimed to examine the stability, tissue permeation and ex vivo muscle-cell effects of microencapsulated gliclazide (G) incorporated with a primary (chenodeoxycholic acid [CDCA]), a secondary (ursodeoxycholic acid [UDCA]) or a tertiary (taurocholic acid [TCA]) bile acid. Materials & methods: Four formulations made of sodium alginate, CDCA, UDCA and TCA were examined for buoyancy, tissue-enhancing effects (in vivo) and local (ex vivo) viability effects. Results & conclusion: CDCA, UDCA and TCA improved buoyancy and cell viability but not tissue-specific uptake. G-TCA-sodium alginate microcapsules exerted hypoglycemic effects, suggesting significant improvement of G gut-uptake by TCA, possibly via improving buoyancy.