Enhancement of ibuprofen solubility and skin permeation by conjugation with l-valine alkyl esters

Abstract

New ibuprofen derivatives were made via conjugation with L-valine alkyl esters (ValOR), where R was changed from an ethyl to a hexyl group. The ionic structure was confirmed using NMR and FTIR. Specific rotation, solubility in commonly used solvents, thermal properties including phase transitions temperatures, and thermal stability were also determined. The ionic structure with a protonated amine group on an L-valine ester and melting points below 100 C allowed inclusion of these ibuprofen derivatives into the pharmaceutically active protic ionic liquids. The ibuprofen salt solubility in deionised water and two buffer solutions at pH 5.4 and 7.4 were established and compared with the parent acid solubility. The octanol/water (buffer) partition coefficient, permeation through porcine skin, and accumulation in the skin were also measured. Ibuprofen pairing with L-valine alkyl esters [ValOR][IBU], caused higher solubility and a greater drug molecule absorption through biological membranes. log P was lower for ibuprofen salts than for the acid and it increased with a longer L-valine ester cation alkyl chain. In vitro porcine skin tests showed that ibuprofen salts with a propyl or isopropyl ester in L-valine are particularly relevant for topical application. They provide transport for ibuprofen through the skin at much higher rate than the unmodified acid and a higher permeated ibuprofen concentration, which can improve efficacy. Thus, synthesised ibuprofen derivatives could be used as drug carriers in transdermal systems to provide better drug bioavailability, and they can be also be the source of exogenous L-valine.

The effect of alcohols as vehicles on the percutaneous absorption and skin retention of ibuprofen modified with l-valine alkyl esters

“…Using previously described a three-step method, 17 we synthesized salts of ibuprofen with L-valine alkyl esters (Scheme 1). The alkyl chain in the L-valine ester group was extended to methyl, heptyl, and octyl group (R) in comparison to the prior described C 2 -C 6 esters.…”

“…However, it is characterized by low solubility (21 mg dm À3 at 25 C in water) and relative high lipophilicity (log P is in the range of 2.41-4.00 the value depends on the measurement method) which result in its poor permeation through the skin. [14][15][16][17][18][19][20][21] Due to the acidic nature (pK a ¼ 4.4), its solubility is dependent on the pH of the environmentit increases with increasing alkalinity: it can vary from 0.024 mg cm À3 (pH ¼ 2.2) to 14.8 mg dm À3 (pH ¼ 9.2). This is closely related to the increase in the ionization degree, which in turn determines the ability of ibuprofen to penetrate the skin.…”

“…In the recent study, we presented the ibuprofen derivatives made by its pairing with some L-valine alkyl esters counterion, which can improve the transport of ibuprofen through porcine skin from ethanol. 17 The presented compounds combine the activity of ibuprofen and an amino acid, and thanks to the form of an alkyl ester, they provide increased water solubility and skin permeability. L-Valine was selected for the research due to the fact that it belongs to the essential exogenous amino acids and is involved in many processes in the body for example inhibits musclebuilding protein degradation process, triggers gluconeogenesis, intensies the secretion of anabolic hormones.…”

Enhancement of the Antioxidant and Skin Permeation Properties of Eugenol by the Esterification of Eugenol to New Derivatives

“…The factor signi cantly affecting the transport of active substances is the lipophilicity of the test compound (Yang et al 2008;Srinivas et al 2019;Ichihashi et al 2003;Casagrande et al 2007). The optimal log P coe cient (which is an indicator of the lipophilicity of the active substance) is in the range of 2 to 3 (Janus et al 2020;Haq et al 2018;Simon et al 2016). This was also con rmed in our own research, which showed that both eugenol and its ester derivatives were characterized by good permeability through the skin (log P: Eugenol 2.20 ± 0.001, EDChA 2.65 ± 0.001, ETChA 2.75 ± 0.002, Table 1).…”

“…This freezing time ensured the stability of the skin barrier properties (Badran et al 2009). Before the examination, the skin was thawed at room temperature for about 30 The integrity of skin was checked one hour after its installation in the Franz diffusion chamber (SES GmbH Analyze Systeme, Germany). Skin impedance was measured using an LCR 4080 meter (Conrad Electronic, Germany) operating in parallel mode at 120 Hz (kΩ error < 0.5%).…”