Polydimethylsiloxane Organic-Inorganic Composite Drug Reservoir with Gliclazide.

A novel organic-inorganic gliclazide-loaded composite bead was developed by an ionic gelation process using acidified CaCl2, chitosan and tetraethylorthosilicate (TEOS) as a crosslinker. The beads were manufactured by crosslinking an inorganic silicone elastomer (-OH terminated polydimethylsiloxane, PDMS) with TEOS at different ratios before grafting onto an organic backbone (Na-alginate) using a 32 factorial experimental design. Gliclazide's encapsulation efficiency (EE%) and drug release over 8 h (% DR 8 h) were set as dependent responses for the optimisation of a pharmaceutical formula (herein referred to as 'G op') by response surface methodology. EE % and %DR 8 h of G op were 93.48% ± 0.19 and 70.29% ± 0.18, respectively. G op exhibited a controlled release of gliclazide that follows the Korsmeyer-Peppas kinetic model (R2 = 0.95) with super case II transport and pH-dependent swelling behaviour. In vitro testing of G op showed 92.17% ± 1.18 cell viability upon testing on C2C12 myoblasts, indicating the compatibility of this novel biomaterial platform with skeletal muscle drug delivery.

Biochemical changes to the inner ear contributing to diabetes-induced hearing loss: possible pharmacological targets for therapy.

OBJECTIVES: Biochemical alterations due to diabetes development and progress are complex and diabetes-associated injury to various tissues has been well reported. Nevertheless, a close investigation of the literature demonstrates limited coverage regarding these biochemical and molecular alterations within the inner ear and their impact on the vestibulocochlear environment. A closer look at these may reveal pharmacological targets that could alleviate the severity of disease in patients. KEY FINDINGS: Tight control of glucose levels within the highly metabolic inner ear structures is crucial for their physiology and function. Impaired glucose homeostasis is well known to occur in vestibulocochlear malfunctioning. Moreover, the involvement of insulin signalling, and glucose transporters were recently confirmed in vestibulocochlear structures and are believed to play a crucial role in auditory and vestibular functions. CONCLUSION: Oxidative overload, glucolipotoxicity, perturbed blood rheology, endothelial dysfunction, compromised microvascular supply, and neurotoxicity are reported in many diabetic complications such as nephropathy, retinopathy, and diabetic neuropathy and are incriminated in the disruption of blood labyrinth barrier as well as vestibulocochlear neuritis. Dysfunctional insulin signalling was recently reported in the Organ of Corti. Insulin resistance in the inner ear niche warrants further studies to verify and uncover new pharmacological targets to manage this debilitating condition better.

Novel Silicone-Grafted Alginate as a Drug Delivery Scaffold: Pharmaceutical Characterization of Gliclazide-Loaded Silicone-Based Composite Microcapsules.

A novel gliclazide-loaded elastomeric carbohydrate pharmaceutical vehicle was successfully developed. This new siliconized alginate platform showed pseudoplastic rheology with a zeta potential ranging from (-43.8 mV to -75.5 mV). A Buchi-B390 encapsulator was employed to formulate different types of silicone-grafted alginate microcapsules loaded with gliclazide relying on the vibrational ionic gelation technology. The use of tetraethyl orthosilicate (TEOS) to crosslink the silicone elastomer (hydroxy terminated polydimethylsiloxane) of this new platform had improved the gliclazide encapsulation (>92.13% ± 0.76) of the free-flowing composite microcapsules, which showed good mechanical durability (up to 12 h in PBS pH 6.8) and promising results to sustain the drug release.

Role of metformin in various pathologies: state-of-the-art microcapsules for improving its pharmacokinetics.

Metformin was originally derived from a botanical ancestry and became the most prescribed, first-line therapy for Type 2 diabetes in most countries. In the last century, metformin was discovered twice for its antiglycemic properties in addition to its antimalarial and anti-influenza effects. Metformin exhibits flip-flop pharmacokinetics with limited oral bioavailability. This review outlines metformin pharmacokinetics, pharmacodynamics and recent advances in polymeric particulate delivery systems as a potential tool to target metformin delivery to specific tissues/organs. This interesting biguanide is being rediscovered this century for multiple clinical indications as anticancer, anti-aging, anti-inflammatory, anti-Alzheimer's and much more. Microparticulate delivery systems of metformin may improve its oral bioavailability and optimize the therapeutic goals expected.

Polydimethylsiloxane-customized nanoplatform for delivery of antidiabetic drugs.

Aim: To develop a new self-emulsified silicon-grafted-alginate platform for pharmaceutical delivery. The produced biocompatible polymeric blend would be used to encapsulate metformin by a vibrational jet-flow ionotropic gelation process. Materials & methods: Polydimethylsiloxane was homogenized with alginate to prepare a stable polymeric mixture to which metformin was added. A metformin-loaded polymeric vehicle was then pumped through Buchi B-390 into CaCl2 to produce microcapsules. Results & conclusion: The platform showed a powerful, pseudoplastic thixotropic and demonstrated strong, efficient and wide applications of polydimethylsiloxane-customized technology in drug delivery and stability. A substantial improvement in drug loading, encapsulation efficiency and flow properties were noticed in siliconized microcapsules compared with the control.

Micro-Nano formulation of bile-gut delivery: rheological, stability and cell survival, basal and maximum respiration studies.

Probucol (PB) is a drug that exhibits significant hydrophobicity and substantial intra and inter individual variability in oral absorption, with a miniature bioavailability and complex three compartmental pharmacokinetic modelling due to its high lipid affinity, low stability and high octanol to water partition coefficient. Multiple attempts to formulate PB have not produced satisfactory stable matrices, drug-release profile or rheological flow properties for optimum manufacturing conditions, and with positive and none toxic biological effects. Lithocholic acid (LCA) has recently shown to optimise formulation and cell uptake of drugs. Hence, the aim of this study was to design new PB delivery system, using LCA, and examine its morphology, rheology, stability, and cellular effects. PB was formulated with LCA and sodium alginate (PB-LCA-SA) using various microencapsulation methodologies, and best formulation was investigated in vitro and ex vivo. Using our Ionic Gelation Vibrational Jet flow technology, PB-LCA-SA microcapsules showed good stability and significantly enhanced cell viability, cellular respiration, and reduced inflammation suggesting potential LCA applications in PB delivery and biological effects.

Advanced and multifaceted stability profiling of the first-line antidiabetic drugs metformin, gliclazide and glipizide under various controlled stress conditions.

The antidiabetic drugs metformin, gliclazide and glipizide have been widely used and studied in terms of pharmacological and antidiabetic effects, and their individual stability has been studied in the literature. However, the drugs' combined stability profiling remains poorly understood, and hence the aim of this study was to investigate the collective stability profiling of different combinations at various controlled conditions. Degradation assessments were carried out on metformin, glipizide and gliclazide by applying a stability-indicating HPLC method that was developed and validated in accordance with ICH guidelines. Glipizide, gliclazide, metformin and the binary mixtures (metformin/glipizide and metformin/gliclazide) were subjected to different forced degradation conditions and were detected at 227 nm by an isocratic separation on an Alltima CN column (250 mm × 4.6 mm × 5µ) utilizing a mobile phase that consists of 20 mM ammonium formate buffer (pH 3.5) and acetonitrile at a ratio of (45:55, v/v). The method is linear (R2 = 0.9999) at the concentration range 2.5-150 µg/ml for metformin and 1.25-150 µg/ml for sulfonylureas respectively and offers a specific and sensitive tool for their determination in <10 min chromatographic run. All drug peaks were sharp and well separated. Stress degradation revealed that metformin has a remarkable sensitivity to alkaline stress, glipizide was more sensitive to thermal degradation while gliclazide exhibited almost full degradation in acidic, alkaline and oxidative stress conditions.

Development and validation of a new analytical HPLC method for simultaneous determination of the antidiabetic drugs, metformin and gliclazide.

An efficient and simple HPLC method has been developed and validated for the simultaneous determination of gliclazide and metformin hydrochloride in bulk and was applied on marketed metformin and gliclazide products. The mobile phase used for the chromatographic runs consisted of 20 mM ammonium formate buffer (pH 3.5) and acetonitrile (45:55, v/v) The separation was achieved on an Alltima CN (250 mm × 4.6 mm x5µ) column using isocratic mode. Drug peaks were well separated and were detected by a UV detector at 227 nm. The method was linear at the concentration range 1.25-150 µg/ml for gliclazide and 2.5-150 µg/ml for metformin respectively. The method has been validated according to ICH guidelines with respect to system suitability, specificity, precision, accuracy and robustness. Metformin limit of detection (LOD) and limit of quantification (LOQ) were 0.8 µg/ml and 2.45 µg/ml respectively while LOD and LOQ for gliclazide were 0.97 µg/ml and 2.95 µg/ml respectively.

Oral insulin delivery: existing barriers and current counter-strategies.

OBJECTIVES: The chronic and progressive nature of diabetes is usually associated with micro- and macrovascular complications where failure of pancreatic ß-cell function and a general condition of hyperglycaemia is created. One possible factor is failure of the patient to comply with and adhere to the prescribed insulin due to the inconvenient administration route. This review summarizes the rationale for oral insulin administration, existing barriers and some counter-strategies trialled. KEY FINDINGS: Oral insulin mimics the physiology of endogenous insulin secreted by pancreas. Following the intestinal absorption of oral insulin, it reaches the liver at high concentration via the portal vein. Oral insulin on the other hand has the potential to protect pancreatic ß-cells from autoimmune destruction. Structural modification, targeting a particular tissue/receptor, and the use of innovative pharmaceutical formulations such as nanoparticles represent strategies introduced to improve oral insulin bioavailability. They showed promising results in overcoming the hurdles facing oral insulin delivery, although delivery is far from ideal. SUMMARY: The use of advanced pharmaceutical technologies and further research in particulate carrier system delivery predominantly nanoparticle utilization would offer useful tools in delivering insulin via the oral route which in turn would potentially improve diabetic patient compliance to insulin and the overall management of diabetes.