Development of a Versatile Lipid Core for Nanostructured Lipid Carriers (NLCs) Using Design of Experiments (DoE) and Raman Mapping.

The objective of this study was to develop a versatile lipid core for the 'brick-dust type of drugs' (poorly water-soluble and poorly lipid-soluble drugs). In the first step, excipients of different polarities were classified according to their behavior in aqueous solutions. Subsequently, binary mixtures were prepared with cetyl palmitate (Crodamol™ CP pharma, Campinas, São Paulo, Brazil) as the solid lipid, and its miscibility with other excipients was evaluated using Raman mapping and classical least squares (CLS). Based on the results, the excipients Crodamol™ CP pharma (hydrophobic), Super Refined™ DMI (dimethyl isosorbide; hydrophilic, Mill Hall, PA, USA), and Super Refined™ Lauryl Lactate (lauryl lactate, medium polarity, Mill Hall, PA, USA) were chosen to compose the lipid core. The ideal proportion of these excipients was determined using a mixture design and the standard deviation (STD) of image histograms as the response variables. After statistical evaluation of the DoE results, the final composition was determined, and drugs with different logP (0 to 10) and physicochemical characteristics were evaluated in the optimized mixture. The drugs butamben (Sigma-Aldrich Co., Spruce Street, St. Louis, MO, USA), tacrolimus (NutriFarm, São Paulo, Brazil), atorvastatin calcium, and resveratrol (Botica da Terra, Campinas, Brazil) presented a homogeneous distribution in the optimized lipid core, indicating that this is a promising system to be used in nanostructured lipid carrier (NLC) formulations of such types of drugs.

Development of a Versatile Nanostructured Lipid Carrier (NLC) Using Design of Experiments (DoE)-Part II: Incorporation and Stability of Butamben with Different Surfactants.

Nanostructured lipid carriers (NLCs) are typically composed of liquid lipids, solid lipids, and surfactants, enabling the encapsulation of lipophilic drugs. Butamben is a Class II anesthetic drug, according to the Biopharmaceutical Classification System (BCS); it has a log P of 2.87 and is considered a 'brick dust' (poorly water-soluble and poorly lipid-soluble) drug. This characteristic poses a challenge for the development of NLCs, as they are not soluble in the liquid lipid present in the NLC core. In a previous study, we developed an NLC core consisting of a solid lipid (CrodamolTM CP), a lipophilic liquid with medium polarity (SRTM Lauryl lactate), and a hydrophilic excipient (SRTM DMI) that allowed the solubilization of 'brick dust' types of drugs, including butamben. In this study, starting from the NLC core formulation previously developed we carried out an optimization of the surfactant system and evaluated their performance in aqueous medium. Three different surfactants (CrodasolTM HS HP, SynperonicTM PE/F68, and CroduretTM 40) were studied and, for each of them, a 23 factorial design was stablished, with total lipids, % surfactant, and sonication time (min) as the input variables and particle size (nm), polydispersity index (PDI), and zeta potential (mV) as the response variables. Stable NLCs were obtained using CrodasolTM HS HP and SynperonicTM PE/F68 as surfactants. Through a comparison between NLCs developed with and without SRTM DMI, it was observed that besides helping the solubilization of butamben in the NLC core, this excipient helped in stabilizing the system and decreasing particle size. NLCs containing CrodasolTM HS HP and SynperonicTM PE/F68 presented particle size values in the nanometric scale, PDI values lower than 0.3, and zeta potentials above |10|mV. Concerning NLCs' stability, SBTB-NLC with SynperonicTM PE/F68 and butamben demonstrated stability over a 3-month period in aqueous medium. The remaining NLCs showed phase separation or precipitation during the 3-month analysis. Nevertheless, these formulations could be freeze-dried after preparation, which would avoid precipitation in an aqueous medium.

Distearoyl phosphatidylglycerol and dioleoyl phosphatidylglycerol increase the retention and reduce the toxicity of amphotericin B-loaded in nanoemulsions.

Aim: To develop nanoemulsions (NEs) loading amphotericin B (AmB) and to evaluate the influence of different excipients on the stability and the supramolecular organization, retention and toxicity of AmB. Materials & methods: The NEs were developed from different oils, surfactants, external media and anionic lipids (disteaoryl phosphatidylglycerol [DSPG] and dioleoyl phosphatidylglycerol [DOPG]). Their impact on the size, pH, zeta potential, AmB encapsulation efficiency, AmB retention and hemolytic potential of the NEs was evaluated. Results & conclusion: The use of soybean oil (lipid matrix), Span 80 (surfactant), phosphate buffer (external phase) and DSPG or DOPG (hydrophobic ion pair) provided better NE stability, higher AmB retention within the NEs and a safer formulation profile in hemolysis tests.