Increase of ibuprofen penetration through the skin by forming ion pairs with amino acid alkyl esters and exposure to the electromagnetic field.

A method of increasing the permeability of ibuprofen through the skin using a rotating magnetic field (RMF) is presented. This study evaluated whether 50 Hz RMF modifies ibuprofen's permeability through the skin. Ibuprofen and its structural modifications in the form of ibuprofenates of isopropyl esters of L-amino acids such as L-valine, L-phenylalanine, L-proline, and L-aspartic acid were used in the research. To this end, Franz cells with skin as membrane were exposed to 50 Hz RMF with 5% ibuprofen and its derivatives in an ethanol solution for 48 h. Following the exposures, the amount of penetrated compound was analysed. Regardless of the compound tested, a significant increase in drug transport through the skin was observed. The differences in the first 30 min of permeation are particularly noticeable. Furthermore, it was shown that using RMF increases the permeability of ibuprofen from 4 to 244 times compared to the test without the RMF. The greatest differences were observed for unmodified ibuprofen. However, it is noteworthy that the largest amounts of the active substance were obtained with selected modifications and exposure to RMF. The RMF may be an innovative and interesting technology that increases the penetration of anti-inflammatory and anti-ache drugs through the skin.

Evaluation of the Structural Modification of Ibuprofen on the Penetration Release of Ibuprofen from a Drug-in-Adhesive Matrix Type Transdermal Patch.

This study aimed to evaluate the effect of chemical modifications of the structure of active compounds on the skin permeation and accumulation of ibuprofen [IBU] from the acrylic pressure-sensitive adhesive used as a drug-in-adhesives matrix type transdermal patch. The active substances tested were ibuprofen salts obtained by pairing the ibuprofen anion with organic cations, such as amino acid isopropyl esters. The structural modification of ibuprofen tested were Ibuprofen sodium salt, [GlyOiPr][IBU], [AlaOiPr][IBU], [ValOiPr][IBU], [SerOiPr][IBU], [ThrOiPr][IBU], [(AspOiPr)2][IBU], [LysOiPr][IBU], [LysOiPr][IBU]2, [PheOiPr][IBU], and [ProOiPr][IBU]. For comparison, the penetration of unmodified ibuprofen and commercially available patches was also investigated. Thus, twelve transdermal patches with new drug modifications have been developed whose adhesive carrier is an acrylate copolymer. The obtained patches were characterized for their adhesive properties and tested for permeability of the active substance. Our results show that the obtained ibuprofen patches demonstrate similar permeability to commercial patches compared to those with structural modifications of ibuprofen. However, these modified patches show an increased drug permeability of 2.3 to even 6.4 times greater than unmodified ibuprofen. Increasing the permeability of the active substance and properties such as adhesion, cohesion, and tack make the obtained patches an excellent alternative to commercial patches containing ibuprofen.

Influence of the Type of Amino Acid on the Permeability and Properties of Ibuprofenates of Isopropyl Amino Acid Esters.

Modifications of (RS)-2-[4-(2-methylpropyl)phenyl] propanoic acid with amino acid isopropyl esters were synthesised using different methods via a common intermediate. The main reaction was the esterification of the carboxyl group of amino acids with isopropanol and chlorination of the amino group of the amino acid, followed by an exchange or neutralisation reaction and protonation. All of the proposed methods were very efficient, and the compounds obtained have great potential to be more effective drugs with increased skin permeability compared with ibuprofen. In addition, it was shown how the introduction of a modification in the form of an ion pair affects the properties of the obtained compound.

New Ferulic Acid and Amino Acid Derivatives with Increased Cosmeceutical and Pharmaceutical Potential.

Ferulic acid (FA) has been widely used in the pharmaceutical and cosmetics industry due to its, inter alia, antioxidant, antiaging and anti-inflammatory effects This compound added to cosmetic preparations can protect skin because of its photoprotective activity. However, the usefulness of FA as a therapeutic agent is limited due to its low solubility and bioavailability. The paper presents the synthesis, identification, and physicochemical properties of new FA derivatives with propyl esters of three amino acids, glycine (GPr[FA]), L-leucine (LPr[FA]), and L-proline (PPr[FA]). The NMR and FTIR spectroscopy, DSC, and TG analysis were used as analytical methods. Moreover, water solubility of the new conjugates was compared with the parent acid. Both ferulic acid and its conjugates were introduced into hydrogel and emulsion, and the resulting formulations were evaluated for stability. Additionally, in vitro penetration of all studied compounds from both formulations and for comparative purposes using Franz diffusion cells was evaluated from the solution in 70% (v/v) ethanol. Finally, cytotoxicity against murine fibroblasts L929 was tested. All of the analyzed compounds permeated pig skin and accumulated in it. LPr[FA] and PPr[FA] were characterized by much better permeability compared to the parent ferulic acid. Additionally, it was shown that all the analyzed derivatives are characterized by high antioxidant activity and lack of cytotoxicity. Therefore, they can be considered as an interesting alternative to be applied in dermatologic and cosmetic preparations.

Novel Naproxen Salts with Increased Skin Permeability.

The paper presents the synthesis, full identification, and characterization of new salts-L-proline alkyl ester naproxenates [ProOR][NAP], where R was a chain from ethyl to butyl (including isopropyl). All obtained compounds were characterized by Nuclear Magnetic Resonance (NMR), Fourier transform infrared spectroscopy (FTIR), X-ray powder diffractometry (XRD), and in vitro dissolution studies. The specific rotation, phase transition temperatures (melting point), and thermal stability were also determined. In addition, their lipophilicity, permeability, and accumulation in pigskin were determined. Finally, toxicity against mouse L929 fibroblast cells was tested. The obtained naproxen derivatives showed improved solubility and higher absorption of drug molecules by biological membranes. Their lipophilicity was lower and increased with the increase in the alkyl chain of the ester. The derivative with isopropyl ester had the best permeability through pigskin. The use of L-proline isopropyl ester naproxenate increased the permeation of naproxen through the skin almost four-fold. It was also shown that the increase in permeability is not associated with additional risk: all compounds had a similar effect on cell viability as the parent naproxen.

Transdermal Delivery Systems for Ibuprofen and Ibuprofen Modified with Amino Acids Alkyl Esters Based on Bacterial Cellulose.

The potential of bacterial cellulose as a carrier for the transport of ibuprofen (a typical example of non-steroidal anti-inflammatory drugs) through the skin was investigated. Ibuprofen and its amino acid ester salts-loaded BC membranes were prepared through a simple methodology and characterized in terms of structure and morphology. Two salts of amino acid isopropyl esters were used in the research, namely L-valine isopropyl ester ibuprofenate ([ValOiPr][IBU]) and L-leucine isopropyl ester ibuprofenate ([LeuOiPr][IBU]). [LeuOiPr][IBU] is a new compound; therefore, it has been fully characterized and its identity confirmed. For all membranes obtained the surface morphology, tensile mechanical properties, active compound dissolution assays, and permeation and skin accumulation studies of API (active pharmaceutical ingredient) were determined. The obtained membranes were very homogeneous. In vitro diffusion studies with Franz cells were conducted using pig epidermal membranes, and showed that the incorporation of ibuprofen in BC membranes provided lower permeation rates to those obtained with amino acids ester salts of ibuprofen. This release profile together with the ease of application and the simple preparation and assembly of the drug-loaded membranes indicates the enormous potentialities of using BC membranes for transdermal application of ibuprofen in the form of amino acid ester salts.

Salicylic Acid as Ionic Liquid Formulation May Have Enhanced Potency to Treat Some Chronic Skin Diseases.

In recent years, numerous studies have shown that conversion of conventional drugs in ionic liquid (IL) formulation could be a successful strategy to improve their physicochemical properties or suggest a new route of administration. We report the synthesis and detailed characterization of eight salicylic acid-based ILs (SA-ILs) containing cation non-polar or aromatic amino acid esters. Using in vitro assays, we preliminary evaluated the therapeutic potency of the novel SA-ILs. We observed that conversion of the SA into ionic liquids led to a decrease in its cytotoxicity toward NIH/3T3 murine embryo fibroblasts and human HaCaT keratinocytes. It should be mentioned is that all amino acid alkyl ester salicylates [AAOR][SA] inhibit the production of the proinflammatory cytokine IL-6 in LPS-stimulated keratinocytes. Moreover, keratinocytes, pretreated with [PheOMe][SA] and [PheOPr][SA] seem to be protected from LPS-induced inflammation. Finally, the novel compounds exhibit a similar binding affinity to bovine serum albumin (BSA) as the parent SA, suggesting a similar pharmacokinetic profile. These preliminary results indicate that SA-ILs, especially those with [PheOMe], [PheOPr], and [ValOiPr] cation, have the potential to be further investigated as novel topical agents for chronic skin diseases such as psoriasis and acne vulgaris.

Ketoprofen-Based Ionic Liquids: Synthesis and Interactions with Bovine Serum Albumin.

The development of ionic liquids based on active pharmaceutical ingredients (API-ILs) is a possible solution to some of the problems of solid and/or hydrophobic drugs such as low solubility and bioavailability, polymorphism and an alternative route of administration could be suggested as compared to the classical drug. Here, we report for the first time the synthesis and detailed characterization of a series of ILs containing a cation amino acid esters and anion ketoprofen (KETO-ILs). The affinity and the binding mode of the KETO-ILs to bovine serum albumin (BSA) were assessed using fluorescence spectroscopy. All compounds bind in a distance not longer than 6.14 nm to the BSA fluorophores. The estimated binding constants (KA) are in order of 105 L mol-1, which is indicative of strong drug or IL-BSA interactions. With respect to the ketoprofen-BSA system, a stronger affinity of the ILs containing l-LeuOEt, l-ValOBu, and l-ValOEt cation towards BSA is clearly seen. Fourier transformed infrared spectroscopy experiments have shown that all studied compounds induced a rearrangement of the protein molecule upon binding, which is consistent with the suggested static mechanism of BSA fluorescence quenching and formation of complexes between BSA and the drugs. All tested compounds were safe for macrophages.

A new experimental measurement and planning tool for sonographic-assisted navigation.

In this study, we present a new 2.5-dimensional ultrasonic navigation system for measuring axes, lengths, and torsions preoperatively, intraoperatively, and postoperatively. The system comprises an ultrasound unit with a 5-MHz linear probe (TELEMED Echoblaster 128; Telemed, Vilnius, Lithuania) and a navigation system (OrthoPilot; B. Braun Aesculap, Tuttlingen, Germany) with a Polaris camera (Northern Digital, Waterloo, Canada). Specialized software developed for this application allows for selecting any body region on a virtual 3D skeleton. With a virtual ultrasound probe, planes needed for measurements can be defined. For each section, the respective surface contour of the bone, which is also shown in the ultrasound image, is displayed. Alternatively, the clinician can use established standard sections. Finally, the required length, axes, and torsions are defined. The accuracy and precision of the system were tested using a plastic model. The measurements of length, torsion, and axis values were accurate to -0.1 +/- 0.3 mm (95% CI), 0.1 degree +/- 0.2 degree (95% CI), and 0.0 degree +/- 0.006 degree (95% CI), respectively. The precision variances for length, torsion, and axis were 1.17 mm (standard deviation) and 0.94 degree and 0.66 degree. These results suggest that the new sonographic method is more accurate than conventional radiographic techniques.