Development of Dapagliflozin Solid Lipid Nanoparticles as a Novel Carrier for Oral Delivery: Statistical Design, Optimization, In-Vitro and In-Vivo Characterization, and Evaluation

Determination of Solubility of Solid Lipids and Surfactants

Controlling hyperglycemia and avoiding glucose reabsorption are significant goals in type 2 diabetes treatments. Among the numerous modes of medication administration, the oral route is the most common. Introduction: Dapagliflozin is an oral hypoglycemic agent and a powerful, competitive, reversible, highly selective, and orally active human SGLT2 inhibitor. Dapagliflozin-loaded solid lipid nanoparticles (SLNs) are the focus of our present investigation. Controlled-release lipid nanocarriers were formulated by integrating them into lipid nanocarriers. The nanoparticle size and lipid utilized for formulation help to regulate the release of pharmaceuticals over some time.

Dapagliflozin-loaded nanoparticles were formulated by hot homogenization followed by ultra-sonication. The morphology and physicochemical properties of dapagliflozin-SLNs have been characterized using various techniques. The optimized dapagliflozin-SLNs have a particle size ranging from 100.13 ± 7.2 to 399.08 ± 2.4 nm with 68.26 ± 0.2 to 94.46 ± 0.7% entrapment efficiency (%EE). Dapagliflozin-SLNs were optimized using a three-factor, three-level Box–Behnken design (BBD). Polymer concentration (X1), surfactant concentration (X2), and stirring duration (X3) were chosen as independent factors, whereas %EE, cumulative drug release (%CDR), and particle size were selected as dependent variables.

Interactions between drug substances and polymers were studied using Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and atomic force microscopy (AFM) analysis indicated the crystalline change from the drug to the amorphous crystal. Electron microscope studies revealed that the SLNs’ structure is nearly perfectly round. It is evident from the findings that dapagliflozin-SLNs could lower elevated blood glucose levels to normal in STZ-induced diabetic rats, demonstrating a better hypoglycemic impact on type 2 diabetic patients. The in vivo pharmacokinetic parameters of SLNs exhibited a significant rise in C_max (1258.37 ± 1.21 mcg/mL), AUC (5247.04 mcg/mL), and oral absorption (2-fold) of the drug compared to the marketed formulation in the Sprague Dawley rats.

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Materials and Methods

Materials

Dapagliflozin was obtained as a gift sample from Hetero Drugs Lab (Hyderabad, India). Poloxamer-188, stearic acid (SA), and cetostearyl alcohol (CSA) phospholipids were procured from Research-lab fine chem industries in Mumbai; glycerol monostearate, Mohini Organics Pvt. Ltd. (Mumbai, India), Bangalore provided Tween 80, methanol, and chloroform. SD fine chemicals Pvt. Ltd., Mumbai, India, provided Precirol^® ATO5 and Compritol^® 888 ATO.

Measurement of Dapagliflozin Solubility in Lipids

The solubility studies were not performed due to the solid nature of the lipids; a different method was used to determine the drug’s solubility in solid lipids. In brief, 10 mg of dapagliflozin was precisely weighed and placed in a screw-capped glass bottle with an aluminum foil covering. About 200 mg of lipid (stearic acid, cetostearyl alcohol, GMS, Precirol ATO5, and Compritol 888ATO) was added to the bottle and cooked at 80 °C while swirling continuously. Then, more lipid was added in small increments while constantly stirring and heating at 80 °C until a clear solution was created. The mixture was centrifuged for 10 min at 6000 rpm (Remi centrifuge) to separate the aqueous phase. After suitable dilution in triplicate, the concentration of dapagliflozin in the aqueous phase was determined using a UV spectrophotometer (UV-1800, Shimadzu, Japan). The entire amount of lipid added to achieve a clear solution was monitored.

Selection of Appropriate Surfactant

First, 1 mL surfactant (Tween 20, Tween 80, PEG200, Limonene, and Cremophore EL) was added to an Eppendorf tube, and the excess dapagliflozin and the tube were shaken for 15 min. The mixture was left to stand for 72 h in an orbital shaker. After centrifuging the mixture at 5000 rpm for 15 min, the supernatant was collected and separated. After proper dilution, the amount of dapagliflozin was determined at 235 nm using a UV–Vis spectrophotometer (Shimadzu, 1800, Tokyo, Japan).

Unnisa, A.; Chettupalli, A.K.; Al Hagbani, T.; Khalid, M.; Jandrajupalli, S.B.; Chandolu, S.; Hussain, T. Development of Dapagliflozin Solid Lipid Nanoparticles as a Novel Carrier for Oral Delivery: Statistical Design, Optimization, In-Vitro and In-Vivo Characterization, and Evaluation. Pharmaceuticals 2022, 15, 568. https://doi.org/10.3390/ph15050568

excipients formulation