A comprehensive approach to transdermal drug delivery through the skin: Ibuprofen derivatives in semi-solid formulations

Abstract. This article presents a comprehensive study on the formulation and evaluation of pharmaceutical emulsions for topical drug delivery. The research focused on emulsions containing ibuprofen and its derivatives (sodium and L-lysine propyl ester salts), investigating their solubility, consistency, stability, and skin permeation. The study offers valuable insights into the development of effective pharmaceutical products. Background. Transdermal and topical drug delivery is a promising approach for the treatment of various medical conditions. Pharmaceutical emulsions provide an ideal platform for delivering active substances through the skin. The selection of emulsion ingredients, consistency, and stability play a critical role in determining the suitability of these formulations. Aim of the study. The primary aim of this study was to formulate and evaluate pharmaceutical emulsions containing ibuprofen and other active substances. Key objectives included assessing solubility, consistency, stability, and skin permeation characteristics of the emulsions. The study aimed to provide insights into the development of effective topical drug delivery systems. Material and methods. Solubility tests were conducted to select suitable emulsion ingredients. Various emulsions were prepared with different water-to-oil phase ratios. Rheology modifiers were added to enhance consistency. Quality control assessments were performed, including uniformity, consistency, stability, density, viscosity, and particle size analysis. The release of active substances from the formulations and their penetration and accumulation in the skin were determined. Results. The results revealed variations in viscosity, consistency, and stability among different formulations. Emulsion-based preparations demonstrated the highest accumulation of active substances in the skin, with formulation F1 (5294.617 μg/g skin) exhibiting the most promising results. The highest release of ibuprofen was observed from the formulation based on Celugel with the addition of [LysOPr][IBU] (F6) - approximately 7750 μg IBU/cm2, and the highest penetration of the active substance was obtained for the emulsion with the addition of IBU∙Na (F2) - 3300 μg IBU/cm2 after 24 hours of testing. Conclusion. This comprehensive study on pharmaceutical emulsions for topical drug delivery provides critical insights into the formulation and evaluation of cosmetic and pharmaceutical products. The findings highlight the importance of ingredient selection, consistency, and stability in the development of effective emulsion-based formulations. Furthermore, the study suggests that emulsion-based preparations have potential for topical applications, especially for more hydrophilic active substances. Future research can build on these results to enhance drug delivery systems and improve patient outcomes

Comparison of antioxidant activity of extracts of hop leaves harvested in different years

Introduction: Hop (Humulus lupulus L.) is a common plant in Europe, with many beneficial health effects. In addition to the use in brewing, hops are a valuable source of active substances used in conventional and folk medicine, such as humulones and lupulones, as well as antioxidants, including phenolic compounds. Objective: The aim of the study was to evaluate and compare the antioxidant activity of alcoholic extracts of fresh hop leaves collected in 2017 and 2018. Material and methods: The raw material consisting of fresh hop leaves was extracted using ultrasoundassisted extraction. Methyl, ethyl and isopropyl alcohol at three concentrations were used as extractants. The antioxidant activity of extracts was determined using DPPH and FRAP methods. Total phenolic content was evaluated using the Folin-Ciocalteu technique. Results: All the extracts showed antioxidant potential as well as the phenolic content. Regardless of the harvesting year and methods of evaluation, the highest antioxidant activity and the total polyphenol content were observed for extracts prepared in undiluted methanol, obtained during one hour lasting extraction. Conclusion: The results of the studies have suggested that hop leaves can be a potential source of healthpromoting antioxidants

Comparison of antioxidant activity of extracts of hop leaves harvested in different years

Introduction: Hop (Humulus lupulus L.) is a common plant in Europe, with many beneficial health effects. In addition to the use in brewing, hops are a valuable source of active substances used in conventional and folk medicine, such as humulones and lupulones, as well as antioxidants, including phenolic compounds. Objective: The aim of the study was to evaluate and compare the antioxidant activity of alcoholic extracts of fresh hop leaves collected in 2017 and 2018. Material and methods: The raw material consisting of fresh hop leaves was extracted using ultrasoundassisted extraction. Methyl, ethyl and isopropyl alcohol at three concentrations were used as extractants. The antioxidant activity of extracts was determined using DPPH and FRAP methods. Total phenolic content was evaluated using the Folin-Ciocalteu technique. Results: All the extracts showed antioxidant potential as well as the phenolic content. Regardless of the harvesting year and methods of evaluation, the highest antioxidant activity and the total polyphenol content were observed for extracts prepared in undiluted methanol, obtained during one hour lasting extraction. Conclusion: The results of the studies have suggested that hop leaves can be a potential source of healthpromoting antioxidants

Comparison of antioxidant activity of extracts of hop leaves harvested in different years

Introduction: Hop (Humulus lupulus L.) is a common plant in Europe, with many beneficial health effects. In addition to the use in brewing, hops are a valuable source of active substances used in conventional and folk medicine, such as humulones and lupulones, as well as antioxidants, including phenolic compounds

Exploring Alkyl Ester Salts of L-Amino Acid Derivatives of Ibuprofen: Physicochemical Characterization and Transdermal Potential

This research presents novel ibuprofen derivatives in the form of alkyl ester salts of L-amino acids with potential analgesic, anti-inflammatory, and antipyretic properties for potential use in transdermal therapeutic systems. New derivatives of (RS)-2-[4-(2-methylpropyl)phenyl]propionic acid were synthesized using hydrochlorides of alkyl esters (ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and pentyl) of L-glutamine. These were further transformed into alkyl esters of L-amino acid ibuprofenates through neutralization and protonation reactions. Characterization involved spectroscopic methods, including nuclear magnetic resonance and Fourier-transform infrared spectroscopy. Various physicochemical properties were investigated, such as UV–Vis spectroscopy, polarimetric analysis, thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction, water solubility, octanol/water partition coefficient, and permeability through pig skin using Franz diffusion cells. The research confirmed the ionic structure of the obtained hydrochlorides of alkyl esters of L-amino acids and ibuprofenates of alkyl esters of L-glutamic acid. It revealed significant correlations between ester chain length and thermal stability, crystallinity, phase transition temperatures, lipophilicity, water solubility, skin permeability, and skin accumulation of these compounds. Compared to the parent ibuprofen, the synthesized derivatives exhibited higher water solubility, lower lipophilicity, and enhanced skin permeability. This study introduces promising ibuprofen derivatives with improved physicochemical properties, highlighting their potential for transdermal therapeutic applications. The findings shed light on the structure–activity relationships of these derivatives, offering insights into their enhanced solubility and skin permeation, which could lead to more effective topical treatments for pain and inflammation

Enhancement of the Antioxidant and Skin Permeation Properties of Betulin and Its Derivatives

This study investigated the antioxidant activity DPPH, ABTS, and Folin–Ciocalteu methods of betulin (compound 1) and its derivatives (compounds 2–11). Skin permeability and accumulation associated with compounds 1 and 8 were also examined. Identification of the obtained products (compound 2–11) and betulin isolated from plant material was based on the analysis of 1H- NMR and 13C-NMR spectra. The partition coefficient was calculated to determine the lipophilicity of all compounds. In the next stage, the penetration through pig skin and its accumulation in the skin were evaluated of ethanol vehicles containing compound 8 (at a concentration of 0.226 mmol/dm3), which was characterized by the highest antioxidant activity. For comparison, penetration studies of betulin itself were also carried out. Poor solubility and the bioavailability of pure compounds are major constraints in combination therapy. However, we observed that the ethanol vehicle was an enhancer of skin permeation for both the initial betulin and compound 8. The betulin 8 derivative showed increased permeability through biological membranes compared to the parent betulin. The paper presents the transformation of polycyclic compounds to produce novel derivatives with marked antioxidant activities and as valuable intermediates for the pharmaceutical industry. Moreover, the compounds contained in the vehicles, due to their mechanism of action, can have a beneficial effect on the balance between oxidants and antioxidants in the body, minimizing the effects of oxidative stress. The results of this work may contribute to knowledge regarding vehicles with antioxidant potential. The use of vehicles for this type of research is therefore justified

The Changes of Antioxidant Activity of Three Varieties of ‘Nalewka’, a Traditional Polish Fruit Alcoholic Beverage during Long-Term Storage

The diet rich in fruits is widely recommended for health-promoting properties. Regular consumption of fruits could reduce the risk of many diseases. The fruit-based alcoholic beverages have been produced for centuries and, in many countries, are still very popular. ‘Nalewka’ is a traditional name of Polish liqueur, i.e., an alcoholic beverage made by maceration of fruits. Homemade nalewkas are often stored for a long time before consumption, which can affect the content of valuable secondary metabolites. The aim of the study was to compare the effect of long-time storage on antioxidant activity and total polyphenol, total anthocyanin, tannin as well as gallic acid content in three homemade nalewkas. Cherry, plum, and multifruit nalewka were produced in 1997 and between 2013–2019 years. The antioxidant activity was measured by the DPPH, ABTS, FRAP, and CUPRAC methods. The content of gallic acid was estimated by high-performance liquid chromatography (HPLC). The oldest nalewkas (from 1997) showed significantly lower antioxidant activity as well as a lower content of polyphenols, anthocyanins, and gallic acid compared to the later-produced nalewkas, in particular those produced in 2016–2019. In most cases, a correlation was also found between the parameters of antioxidant activity as well as the total content of polyphenols and anthocyanins. Long-term storage of nalewkas reduces the content of valuable secondary metabolites responsible for the antioxidant activity and, thus, the health properties of the beverage

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

<i>Epilobium angustifolium</i> L. Essential Oil—Biological Activity and Enhancement of the Skin Penetration of Drugs—In Vitro Study

Epilobium angustifolium L. is a popular medicinal plant found in many regions of the world. This plant contains small amounts of essential oil whose composition and properties have not been extensively investigated. There are few reports in the literature on the antioxidant and antifungal properties of this essential oil and the possibility of applying it as a potential promoter of the skin penetration of drugs. The essential oil was obtained by distillation using a Clavenger type apparatus. The chemical composition was analyzed by the GC-MS method. The major active compounds of E. angustifolium L. essential oil (EOEa) were terpenes, including α-caryophyllene oxide, eucalyptol, β-linalool, camphor, (S)-carvone, and β-caryophyllene. The analyzed essential oil was also characterized by antioxidant activity amounting to 78% RSA (Radical Scavenging Activity). Antifungal activity against the strains Aspergillus niger, A. ochraceus, A. parasiticum, and Penicillium cyclopium was also determined. The largest inhibition zone was observed for strains from the Aspergillus group. The EOEa enhanced the percutaneous penetration of ibuprofen and lidocaine. After a 24 h test, the content of terpene in the skin and the acceptor fluid was examined. It has been shown that the main compounds contained in the essential oil do not penetrate through the skin, but accumulate in it. Additionally, FTIR-ATR analysis showed a disturbance of the stratum corneum (SC) lipids caused by the essential oil application. Due to its rich composition and high biological activity, EOEa may be a potential candidate to be applied, for example, in the pharmaceutical or cosmetic industries. Moreover, due to the reaction of the essential oil components with SC lipids, the EOEa could be an effective permeation enhancer of topically applied hydrophilic and lipophilic drugs

Bacterial Cellulose Membrane Containing Epilobium angustifolium L. Extract as a Promising Material for the Topical Delivery of Antioxidants to the Skin

Bacterial cellulose membranes (BCs) are becoming useful as a drug delivery system to the skin. However, there are very few reports on their application of plant substances to the skin. Komagataeibacter xylinus was used for the production of bacterial cellulose (BC). The BC containing 5% and 10% ethanolic extract of Epilobium angustifolium (FEE) (BC-5%FEE and BC-10%FEE, respectively) were prepared. Their mechanical, structural, and antioxidant properties, as well as phenolic acid content, were evaluated. The bioavailability of BC-FESs using mouse L929 fibroblasts as model cells was tested. Moreover, In Vitro penetration through the pigskin of the selected phenolic acids contained in FEE and their accumulation in the skin after topical application of BC-FEEs was examined. The BC-FEEs were characterized by antioxidant activity. The BC-5% FEE showed relatively low toxicity to healthy mouse fibroblasts. Gallic acid (GA), chlorogenic acid (ChA), 3,4-dihydroxybenzoic acid (3,4-DHB), 4-hydroxybenzoic acid (4-HB), 3-hydroxybenzoic acid (3-HB), and caffeic acid (CA) found in FEE were also identified in the membranes. After topical application of the membranes to the pigskin penetration of some phenolic acid and other antioxidants through the skin as well as their accumulation in the skin was observed. The bacterial cellulose membrane loaded by plant extract may be an interesting solution for topical antioxidant delivery to the skin