<p>Lipid-Based Gliclazide Nanoparticles for Treatment of Diabetes: Formulation, Pharmacokinetics, Pharmacodynamics and Subacute Toxicity Study</p>

Abstract

Introduction: Solid lipid nanoparticles (SLNs) are considered a promising system in enhancing the oral bioavailability of poorly water-soluble drugs; owing to their intrinsic ability to increase the solubility together with protecting the incorporated drugs from extensive metabolism. Objective: Exploiting such properties, SLNs loaded with gliclazide (GLZ) were developed in an attempt to improve the oral bioavailability and the anti-diabetic action of GLZ, together with prolonging its duration of action for better glycemic control. Methods: SLNs were prepared by ultra-sonication technique using glyceryl behenate (Compritol ® 888 ATO) as a lipid matrix and poloxamer 188 (PLX) as a stabilizer. A 2*3 asymmetrical factorial design was adopted to study the effect of different stabilizer concentrations at different sonication times on the shape, and size of the particles, PDI and drug loading. The selected optimum formulation was then freeze dried using trehalose di-hydrate as a cryo-protectant in different ratios with respect to glyceryl behenate concentration. After freeze drying, the formulation was tested for in-vitro drug release, pharmacokinetics, and pharmacodynamics. Safety of the selected formula was established after carrying out a subacute toxicity study. Results: The factorial design experiment resulted in an optimum formulation coded 10F2 (150 mg PLX/10 min sonication). Scanning electron micrographs showed spherical particles with smooth surface, whereas a ratio of 2:1 cryo-protectant:lipid was found to be optimum with particle size of 245.9 ± 26.2 nm, polydispersity index of 0.482 ± 0.026, and biphasic in-vitro release with an initial burst effect, followed by a prolonged release phase. On the other hand, the selected SLNs exhibited prolonged drug release when compared with the GLZ commercial immediate release (IR) tablets (Diamicron ® ). Pharmacokinetics study showed about 5-fold increase in GLZ oral bioavailability loaded in SLNs when compared with raw GLZ powder. Pharmacodynamics study on a diabetic rat model confirmed the better anti-diabetic action of GLZ loaded SLNs when compared to raw GLZ powder. Subacute toxicity study indicated the safety of SLNs upon repetitive oral administration.

Precisely Fabricated Sulpiride-Loaded Nanolipospheres with Ameliorated Oral Bioavailability and Antidepressant Activity

“…Moreover, upon increasing the surfactant content, the dispersion became slightly viscous, which prevented the partition of SUL in the external aqueous phase. Contrary to the early reported attempt, 42 we did not detect any significant decrease in the % EE upon emulsifier content elevation, which might be due to the difference of either surfactant or drug nature, as well as the range of surfactant concentration chosen. Nevertheless, our findings were supported by previous reports in the literature.…”

“…These are crucial parameters that mainly allow efficient uptake in the intestine, especially in the lymphoid tissue, thus achieving an improvement of drug oral bioavailability. 42 Figure 2 demonstrated the particle and PdI values of several batches of SUL-LPS (F 1 -F 20 ). The particle size of the investigated LPS was in the nanometric range of 49.33 ± 6.46 to 396.9 ± 17.57 nm, along with low PdI values of less than 1, indicating an acceptable dispersion homogeneity.…”

“…Their nanoscale dimensions combined with improved surface area could strongly enhance encapsulated drug diffusion and absorption through the GIT tract. 42 Moreover, their surface decoration with the phospholipid (LS75), one of the cell membrane components, could stimulate SUL integration within the cells. Phospholipid could interact with mucous leading to a slight modulation of the mucosal membrane, an increase in the fluidity of the lipid bilayers and eventually promoting drug penetration along the GIT tract.…”

“… 73 Recently, in vivo subacute toxicity studies, ranging from 14 to 21 days, were reported to initially assess the toxicity of different nanoplatforms. 19 , 42 , 74 …”

Lyophilized Drug-Loaded Solid Lipid Nanoparticles Formulated with Beeswax and Theobroma Oil

“…In order to assure SLN stability, cryoprotectants are typically added to SLN dispersions at concentrations of 10–15% (of the total formulation) prior to lyophilization to reduce particle aggregation and effect reconstitution [ 20 ]. Trehalose is an efficient cryoprotectant for SLN formulations [ 21 , 22 , 23 ]; it was therefore used at a concentration of 10% in the present study.…”