Combined Approach of Cyclodextrin Complexationand Nanostructured Lipid Carriers for the Development of a Pediatric Liquid Oral Dosage Form of Hydrochlorothiazide

Abstract

The development of specific and age-appropriate pediatric formulations is essential to assure that all children and their care-givers can easily access to safe and effective dosage forms. The need for developing specific pediatric medicinal products has been highlighted by the European Medicines Agency. The aim of this study was to investigate the effectiveness of combining the advantages of both cyclodextrin (CD) complexation and loading into nanostructured lipid carriers (NLC), to obtain a liquid oral pediatric formulation of hydrochlorothiazide (HCT), endowed with safety, dosage accuracy, good stability and therapeutic efficacy. Equimolar drug combinations as physical mixture (P.M.) or coground product (GR) with hydroxypropyl-β-cyclodextrin (HPβCD) or sulfobutylether-β-cyclodextrin (SBEβCD) were loaded into NLC, then characterized for particle size, homogeneity, Zeta potential, entrapment efficiency, gastric and storage stability. The presence of HPβCD allowed higher entrapment efficacy than NLC loaded with the plain drug, and enabled, in the case of GR systems a complete and sustained drug release, attributable to the wetting and solubilising properties of HPβCD toward HCT. In vivo studies on rats proved the superior therapeutic effectiveness of HCT-in HPβCD-in NLC formulations compared to the corresponding free HCT-loaded NLC, thus confirming the successfulness of the proposed approach in the development of an efficacious liquid oral formulation of the drug.

Evaluation and Comparison of Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) as Vectors to Develop Hydrochlorothiazide Effective and Safe Pediatric Oral Liquid Formulations

“…As shown in Figure 1 A, the mean diameter of SLNs obtained using Pluronic ® F68 (SLN 1 ) was around 350 nm, significantly smaller than those with Tween ® 80 (SLN 2 ) (above 550 nm). This finding, observed also by other authors [ 22 , 30 , 46 ], has been attributed to a different incorporation way of the two surfactant molecules in the external shell of the nanoparticles [ 47 ].…”

“…Regarding the surfactants, Gelucire ® 44/14, considering its amphiphilic nature (HLB 14), was tested as non-ionic surfactant both in alternative to Tween ® 80 (HLB 15) and Pluronic ® F68 (HLB < 24), used in previous studies [ 22 , 25 , 30 , 31 , 32 ], and also in combination with each of them at different ratios. Gelucire are versatile polymers, consisting in mixtures of glycerides with PEG esters of fatty acids, widely used in drug delivery with different applications, mainly depending on their HLB values [ 33 ].…”

Quality-by-design in pharmaceutical development: From current perspectives to practical applications

“…Besides solid oral dosage form development and optimization, DoE is vastly used in several other pharmaceutical formulation techniques, such as hot melt granulation (69,70), liquid dosage forms (71,72), liposome formulations (73,74) and nanostructured lipid carriers (75).…”

Design, Evaluation and Comparison of Nanostructured Lipid Carriers and Chitosan Nanoparticles as Carriers of Poorly Soluble Drugs to Develop Oral Liquid Formulations Suitable for Pediatric Use

“…NLCs were prepared by hot high-shear homogenization, according to Gonçalves et al [30] and Cirri et al [31]. Briefly, the selected solid (Precirol ® ATO5, alone or in mixture with Gelucire ® 48/16 or stearylamine) and liquid (Transcutol ® HP) lipids were put in a test tube.…”