First in man bioavailability and tolerability studies of a silica–lipid hybrid (Lipoceramic) formulation: a Phase I study with ibuprofen

Abstract

Clinical trials addressing the viability of lipid and nanoparticle-based solid dosage forms for the oral delivery of poorly water-soluble drugs are limited to date. This Phase I study aimed to assess the comparative tolerability and oral pharmacokinetics of a novel silica nanoparticle-lipid hybrid formulation encapsulating ibuprofen (i.e., Lipoceramic-IBU) with reference to a commercial tablet (i.e., Nurofen®). The test (Lipoceramic-IBU) and reference (Nurofen®) ibuprofen formulations were characterised for physicochemical properties and in vitro solubilisation performance prior to the clinical study. A randomised, double-blinded, one-period single oral dose (20 mg ibuprofen) study was performed in 16 healthy male subjects under fasting conditions. Encapsulation of ibuprofen in a molecularly dispersed form in the Lipoceramic nanostructured silica-lipid matrices was shown to produce superior drug solubilisation in comparison to Nurofen® and the pure drug during a two-step dissolution (or solubilisation) study in aqueous buffers of pH 1.2 followed by pH 6.5. Pharmacokinetic profiles revealed an approximately 1.95-fold increased bioavailability (p=0.02) and a 1.5-fold higher maximum plasma concentration (p=0.14) for Lipoceramic-IBU with reference to Nurofen®. Review of the safety assessments, including physical examinations, clinical laboratory tests and reports of adverse events, confirmed negligible acute side effects related to the administration of blank and ibuprofen-loaded Lipoceramic formulations. This first in man study of a dry lipid and nanoparticle-based formulation successfully demonstrated the safe use and effectiveness of the nanostructured Lipoceramic microparticles in mimicking the food effects for optimising the oral absorption of poorly water-soluble compounds.

Solubilization of ibuprofen for freeze dried parenteral dosage forms

“…Various techniques for IBP solubilization in solid oral formulations have been described in the literature: lipid based drug delivery system (8), solid lipid nanoparticles or spray drying of amorphous IBP nanoparticles for the production of granules with enhanced drug release (9,10), solubilization by surfactants (7,11), solid dispersion techniques (12,13), fusion method with Poloxamer 407 (14) and also freeze drying to form IBP crystals (15) or for orodispersible tablet (ODT) formulation (16). The approaches described for liquid formulations are mainly focused on solubility enhancement by cyclodextrin complexation (17,18), addition of hydrotropic agents (19), pH modification (7), surfactant and cosolvent addition (20)(21)(22) and salt formation (23,24).…”

“…Solutions for freeze drying were prepared according to parenteral requirements with regard to tonicity and pH. Quantity of mannitol, glucose, sucrose or sodium chloride was defined by osmolality criteria in a range of 280-320 mosmol kg -1 of reconstituted powder, while the quantity of L-arginine or sodium hydroxide according to pH criteria (following optimal physiological pH of 7.4), which is also in favor of better IBP solubility at pH > 4.5 (8). IBP was dissolved in tertiary butyl alcohol and further mixed with an aqueous solution of NaOH or L-arginine and mannitol, NaCl, sucrose or glucose, followed by filtration through 0.22 µm filters.…”

Improving Ibuprofen solubility by surfactant-facilitated self-assembly into mixed micelles

“…There are different approaches for enhancing IBP delivery: controlled-release formulations [18][19][20], lipid-based drug delivery systems [21][22][23], nano-particles [24,25], vesicles [26] or solubilization by surfactants [27][28][29].…”

Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties: Case Study—Hypromellose (HPMC)

“…As the composition of the studied media (pH, presence of bile salts) will affect drug solubility, two models for the DoE were constructed to discriminate between the effects of excipients on drug solubility in compendial (model 1) and biorelevant conditions (model 2). The examined factors were (i) compound (Table I) Weak acid (pKa=4.5) (32) 4.00 (33) Low (32) determined for each model. A total of 16 × 3 additional experiments for each model were conducted to determine drug solubility in the corresponding media in the absence of excipient.…”