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.     

Ionic Liquids and Salts from Ibuprofen as Promising Innovative Formulations of an Old Drug

Herein we report the synthesis of novel ionic liquids (ILs) and organic salts by combining ibuprofen as anion with ammonium, imidazolium, or pyridinium cations. The methodology consists of an acid–base reaction of neutral ibuprofen with cation hydroxides, which were previously prepared by anion exchange from the corresponding halide salts with Amberlyst A-26(OH). In comparison with the parent drug, these organic salts display higher solubility in water and biological fluids and a smaller degree of polymorphism, which in some cases was completely eliminated. With the exception of [C₁₆Pyr][Ibu] and [N_1,1,2,2OH1][Ibu], the prepared salts did not affect the viability of normal human dermal fibroblasts or ovarian carcinoma (A2780) cells. Therefore, these ibuprofen-based ionic liquids may be very promising lead candidates for the development of effective formulations of this drug.     

静电喷雾法制备聚乳酸/布洛芬微球及其性能研究

采用静电喷雾技术,以聚乳酸（PLA）为骨架载体材料,布洛芬（IBU）为模型药物,成功制备出PLA载IBU微球,利用扫描电子显微镜（SEM）、X射线衍射仪（XRD）、差示扫描量热仪（DSC）、傅里叶变换红外光谱仪（FTIR）、热失重分析仪（TG）和紫外可见分光光度计分析了微球形貌、结构和性能。结果表明,PLA/IBU微球呈表面多孔的无定形结构,分散性较好,IBU以分子或无规则状态负载在PLA中,化学结构未有变化,稳定性较纯IBU有所提高。在体外缓释测试中,PLA/IBU微球相比较纯IBU具有良好的缓释效果,随着投药量的增加,IBU的释放速率和累计释放量逐渐提高,含16 %IBU的PLA微球在48 h内累计释放量可达52 %。静电喷雾法制备的PLA/IBU微球有望提高IBU的生物利用度和溶出率,在生物医药领域具有潜在的应用前景。     

Melt crystallization of ibuprofen on surfaces patterned by a Nd: YAG laser

Surface-based control of melt crystallization of ibuprofen (IBU) is reported. The substrates in the present study included glass, flat Au, and laser-patterned Au. The IBU crystal morphologies were regulated depending on the surfaces where IBU crystallization was induced, and spherical, sunflower-like, and dendritic morphologies were obtained. Especially, the dendritic morphology of a large surface area was observed on the novel laser-patterned surfaces. Three-dimensionally tortuous Au structures were achieved by a 532 nm Nd: YAG laser, of which Gaussian beam profile was reshaped into a flat-top contour using a custom-designed diffusing system. Also, the effect of poly-?-caprolactone was analyzed as a crystallization modulating additive to fine-tune the IBU crystal morphologies. The IBU crystallization behaviors as well as the laser patterning processes are described as a part of the ongoing efforts to develop a general strategy to utilize heterogeneous nucleation and directional growth to control the crystallization of important organic compounds, such as active pharmaceutical ingredients.     

Ibuprofen–polymer precipitation using supercritical CO2 at low temperature

A process for the SAS coprecipitation of ibuprofen with the polymers poly(l-lactic acid) and Eudragit L100 was successfully carried out. The particle size was reduced to micrometer and near nanometer ranges. The morphology of the raw material changed to spherical upon processing for both poly(l-lactic acid)/ibuprofen particles and eudragit/ibuprofen particles. The eudragit-based particles were significantly smaller than those obtained with poly(l-lactic acid). Ibuprofen release profiles were determined for simulated gastric and intestinal fluids in order to study the effect of the polymer and to identify the appropriate systems for different administration routes. The in vitro release profiles for both polymer/drug systems showed a slower and more controlled release in comparison to the unprocessed ibuprofen. Moreover, the effects of pressure, temperature, initial concentration of the solution and drug-to-polymer ratio on the particle size and morphology of these drug/polymer systems have been evaluated. According to the XRD, DSC and FTIR data, physicochemical interactions do not occur between ibuprofen and the polymers and a proportion of the ibuprofen molecules probably remained on the microparticle surface.     

A new way to conduct enzymatic synthesis in an active membrane using ionic liquids as catalyst support

Several active membranes were prepared by immobilization of Candida antarctica lipase B (CALB) onto the surface of ceramic membranes via three different ionic liquids (ILs): [bmim⁺][PF₆⁻], [emim⁺][NTf₂⁻] and [bmim⁺][NTf₂⁻] and compared to an active membrane obtained by simple enzyme adsorption. The performances of these various membranes were evaluated by studying the synthesis of butyl laurate by the acidolysis between butyl acetate and lauric acid in a hexane/water mixture (98:2, v/v). The results obtained show that all the membranes prepared with or without ILs were active and maintained their activity after several runs and during some months.     

布洛芬甲酯的绿色合成工艺

以布洛芬和甲醇为原料,以对甲苯磺酸为催化剂,以甘油作为吸水剂和催化剂分离的溶剂,利用甘油与布洛芬甲酯可自动分层的特性,辅以柱色谱分离,建立了一种布洛芬甲酯的绿色合成工艺。整个工艺路线无三废产生。合成条件经正交实验优化,确定了最佳反应条件:反应体系的最佳组成为n(布洛芬):n(甲醇):n(甘油)=1:10.2:1.4,催化剂对甲苯磺酸的最佳添加量为布洛芬质量的1%,最佳转速为300 r/min,最佳反应时间为4h,在该条件下转化率可达97.1%,得率大于95.0%。经液相-质谱联用(LC/MS)检测,色谱纯度为99.9%。     

改性介孔分子筛对布洛芬的吸附与控制释放

采用合成后改性将氨基嫁接进介孔MCM41和SBA-15孔道内,对功能化的2种分子筛进行药物吸附与控制释放的研究。利用红外光谱仪(IR)、智能重量分析仪(IGA)等表征手段对吸附剂的物理结构和化学组成进行表征。对药物布洛芬(IBU)的吸附量进行比较,结果表明,氨基改性的MCM41(MCM41-NH2)对布洛芬的吸附性能大...     

Tetrabutylphosphonium amino acid ionic liquids as efficient catalysts for solvent-free Knoevenagel condensation reactions

Five tetrabutylphosphonium amino acid ionic liquids ([P₄₄₄₄][AA]) were prepared, characterized, and used as catalysts for solvent-free Knoevenagel condensation reactions. The tetrabutylphosphonium prolinate ([P₄₄₄₄][Pro]) showed excellent catalytic activity and selectivity in Knoevenagel condensation reactions of active methylene compounds with various aromatic aldehydes, and all the yields of corresponding products were more than 85% under mild conditions. Furthermore, a plausible reaction mechanism for the excellent performance of [P₄₄₄₄][Pro] has been proposed, and [P₄₄₄₄][Pro] could be used repetitively at least six times without obvious decrease in activity and quantity.     

布洛芬乙酯的分子筛催化合成

消旋布洛芬乙酯作为微生物拆分消旋药物布洛芬获取ｓ（＋ ）－布洛芬的前体。今采用ＨＺＳＭ－５ 分子筛作为催化剂，消旋布洛芬与乙醇摩尔比为１∶１．２，苯为溶剂及带水剂，成功地合成了消旋布洛芬乙酯。结果表明，反应条件温和，产物容易提纯，产率达９２％ 。产物结构经ＩＲ、ＧＣ－ＭＳ、ＮＭＲ鉴定。     

Designing Simple Lipidated Lysines: Bifurcation Imparts Selective Antibacterial Activity

In the global effort to thwart antimicrobial resistance, lipopeptides are an important class of antimicrobial agents, especially against Gram‐negative infections. In an attempt to circumvent their synthetic complexities, we designed simple membrane‐active agents involving only one amino acid and two lipid tails. Herein we show that the use of two short lipid tails instead of a single long one significantly increases selective antibacterial activity. This study yielded several selective antibacterial compounds, and investigations into the properties of this compound class were conducted with the most active compound. Fluorescence spectroscopic studies revealed the capacity of the representative compound to cause depolarization and permeabilization of bacterial cell membranes. This membrane‐active nature of the compound imparts superior activity against persister cells, biofilms, and planktonic cells. Topical application of the compound decreased bacterial burden in mice inflicted with burn‐infections caused by Acinetobacter baumannii. We anticipate that the design principles described herein will direct the development of several antimicrobial agents of clinical importance.     

Regulating dual temperature- and pH-responsibility constructed from core-shell mesoporous hybrid silica (P(NIPAM-co-AA)@BMMs) via adjusting AA incorporation onto NIPAM

The mesoporous hybrid silicas (P@BMMs) with core-shell structure were successfully synthesized via seed polymerization method using bimodal mesoporous silica materials (BMMs) as core and dual pH- and temperature-responsive poly(N-isopropylacryl-acrylamide)-co-poly(acrylic acid) (P(NIPAM-co-AA)) copolymer as shell. Meanwhile, the obtained P@BMMs were physicochemically and morphologically characterized via X-ray diffraction, N₂ adsorption-desorption isotherms, scanning electron microscopy, transmission electron microscopy, Fourier transform infrared, ultraviolet visible diffused reflection spectrum, small angle X-ray scattering (SAXS), dynamic light scattering, and thermogravimetric analysis techniques. The results indicated that P(NIPAM-co-AA) was successfully coated onto the mesoporous surface of used BMMs, while the uniform mesoporous structure of obtained P@BMMs was still preserved. Using ibuprofen (IBU) as a model drug, the influence of the P(NIPAM-co-AA) shell on the release kinetics of IBU was explored, and its performances elucidated that the P@BMMs nanoparticles presented an apparent thermo/pH-responsive properties, which could be regulated via adjusting mass ratio of AA to NIPAM, and their IBU-release kinetic profiles were favorable to Korsmeyer-Peppas model. Specially, SAXS patterns were employed to evaluate the fractal evolution of P@BMMs along with releasing time, showing the decline tendency for mass fractal value from 2.89 to 2.56 during the release time of 0.25–24?h.     

介孔水化硅酸钙微球的形貌控制及载药性能研究

以氢氧化钙和正硅酸四乙酯为原料,采用共沉淀法制备出了一系列的水化硅酸钙(CSH),通过X射线衍射(XRD)、扫描电子显微镜(SEM)等探讨了不同的酒精添加量和有机溶剂添加对CSH的物相和形貌的影响。结果表明;随着酒精添加量的增加CSH的分散性逐渐变好,采用丙三醇作为有机溶剂可以得到分散较好CSH微球。对CSH进行了布洛芬(IBU)载药研究,利用热重-差热分析、Brunauer-Emmett-Teller法和红外光谱表征(FT-IR)合对其在不同载药时间的CSH载药量、比表面积、孔容和表面基团等进行了分析。发现在12 h后载药量达到116.78%,有望成为较好的药物载体材料。     

Study on the release behavior and mechanism by monitoring the morphology changes of the large‐sized drug‐LDH nanohybrids

Mg‐Al layered double hydroxide (LDH) nanohybrids intercalated with ibuprofen (IBU) with particle sizes of 150–530 nm have been synthesized through hydrothermal and coprecipitation treatment in aqueous solution without any organic solvent. The in vitro drug release properties of as‐prepared IBU‐LDH nanohybrids are systematically studied and the kinetic simulation to the release profiles suggests that the release processes of the larger nanohybrids are mainly controlled by intraparticle diffusion. The morphology changes from thick sheet‐like into thin margin‐curved platelets for the larger nanohybrid particles, induced by the hydrophobic IBU anions aggregations located in the edge region of interlayer via ion‐exchange diffusion process, is firstly observed during the release process. Based on the SEM, HRTEM, XRD, FTIR, and UV‐vis analyses of the samples recovered at different release time, a release mechanism model of the as‐prepared IBU‐LDH nanohybrids is tentatively proposed along with their morphology changes during the whole release process. © 2010 American Institute of Chemical Engineers AIChE J, 2011     

Ibuprofen Favors Binding of Amyloid-β Peptide to Its Depot,Serum Albumin

The deposition of amyloid-β peptide (Aβ) in the brain is a critical event in the progression of Alzheimer’s disease (AD). This Aβ deposition could be prevented by directed enhancement of Aβ binding to its natural depot, human serum albumin (HSA). Previously, we revealed that specific endogenous ligands of HSA improve its affinity to monomeric Aβ. We show here that an exogenous HSA ligand, ibuprofen (IBU), exerts the analogous effect. Plasmon resonance spectroscopy data evidence that a therapeutic IBU level increases HSA affinity to monomeric Aβ₄₀/Aβ₄₂ by a factor of 3–5. Using thioflavin T fluorescence assay and transmission electron microcopy, we show that IBU favors the suppression of Aβ₄₀ fibrillation by HSA. Molecular docking data indicate partial overlap between the IBU/Aβ₄₀-binding sites of HSA. The revealed enhancement of the HSA–Aβ interaction by IBU and the strengthened inhibition of Aβ fibrillation by HSA in the presence of IBU could contribute to the neuroprotective effects of the latter, previously observed in mouse and human studies of AD.     

Thermal and electrochemical properties of morpholinium salts with bromide anion

The present work is a study of the thermal properties and electrochemical stabilities of N-ethyl-N-methylmorpholinium bromide ([Mor_1,2][Br]), N-butyl-N-methylmorpholinium bromide ([Mor1_1,4][Br]), N-octyl-N-methylmorpholinium bromide ([Mor1_1,8][Br]), N-dodecyl-N-methylmorpholinium bromide ([Mor1_1,12][Br]), and N,N-dihydroxyethylmorpholinium bromide ([DHEMor][Br]). The melting points, decomposition temperatures, and electrochemical stabilities of the salts were measured by DSC (differential scanning calorimetry), TGA (thermogravimetric analysis), and CV (cyclic voltammogram), respectively. All salts were decomposed below approximately 230.00 °C and their melting points were above 100.00 °C except [DHEMor][Br], which melted at 75.17 °C. [DHEMor][Br] appeared to possess the most wide liquid-phase range between melting point and decomposition temperature. The electrochemical windows of salts ranged from 3.3 V for [Mor_1,8][Br] to 3.6 V for [Mor_1,4][Br] and thus did not show any noticeable variation with cations used for salt synthesis.     

New quaternary benzyl chloride salts for inclusion in hair cream rinse formulations

Quaternary ammonium salts have been prepared from benzyl chloride and amino amides and an amino ester of a long chain fatty acid. These benzyl salts were incorporated in simple hair conditioner formulations containing the quaternary salt, anhydrous lanolin, cetyl alcohol, and water. Preliminary evaluations indicated that the formulations were effective in the removal of tangles and snarls following washing with ordinary shampoo. The dried hair was easily manageable and had good luster.     

Efficient Synthesis of Octacosanol Linoleate Catalyzed by Ionic Liquid and Its Structure Characterization

Octacosanol, as the major active policosanol, has attracted much attention due to the potential beneficial effects for human health. However, free octacosanol has a high melting point, poor oil solubility and low bioavailability, which greatly restricts its practical application. In this study, we report a highly efficient method for an ionic liquids (IL)‐catalyzed synthesis of octacosanol ester by direct esterification with linoleic acid. The synthesized product was purified, subsequently characterized by FT‐IR, MS and NMR and finally confirmed to be octacosanol linoleate. The reaction parameters were investigated and the conversion reached 91.3 ± 4.8 % under the optimum conditions: IL 1‐butylsulfonate‐3‐methylimidazolium hydrogen sulfate ([BSO₃HMim][HSO₄]) as catalyst, IL dose 1.5 % (related to the mass of both reactants), 1:1 molar ratio of octacosanol to linoleic acid, 80 °C, and 1 h. The melting point and oil solubility of octacosanol were greatly improved by esterification with linoleic acid, facilitating the incorporation into a variety of oil‐based systems.     

Controlling drug delivery from polymer microspheres by exploiting the complex interrelationship of excipient and drug crystallization

Semicrystalline polymers are often used as macromolecular excipients in active pharmaceutical ingredient (API)-delivery systems. In such systems, the morphological structure and crystalline characteristics of the excipient have a direct impact upon the drug-delivery rate. In this study, polycaprolactone (PCL)-based microspheres prepared via melt-printing were loaded with 10, 30, and 50% ibuprofen (IBU). In vitro release studies showed that, for a constant amount of IBU, the API was released fastest from the 30%-loaded microspheres, followed by the 50%- and 10%-loaded microspheres. The discrepancy in these release rates was investigated using scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and thermodynamic analyses, revealing the complex morphological and crystalline interrelationships of PCL and IBU. Although it is generally accepted that the degree of crystallinity of the excipient is the main factor controlling the release of the API, we found that the crystallite size of the small-molecule API is of primary importance. Moreover, these factors, which are controllable via the parameters used in melt-based preparation, can be exploited to tune drug-release rates. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47227.