Drug In Aqueous Solution Research Articles

Aggregation behaviour of betablocker drugs in aqueous media

The presence of pharmaceutical chemicals in the aquatic environment is a cause of concern. Knowledge of the behaviour of these compounds in water is important to identify and comprehend the consequences of their occurrence in the environment. For a better understanding of the aqueous behaviour of some pharmaceuticals, the critical aggregation concentration (cac) of several drugs in aqueous solution has been measured at 298.15 K through density (ρ), speed of sound (u) and conductivity (κ) measurements. In addition, isentropic compressibilities (κs) have been calculated from the experimental data. Moreover, solubilities have been obtained at the same temperature and the partition coefficients have been calculated theoretically using the ALOGPS method.

Penetration enhancers in proniosomes as a new strategy for enhanced transdermal drug delivery

The aim of this work is to investigate penetration enhancers in proniosomes as a transdermal delivery system for nisoldipine. This was performed with the goal of optimising the composition of proniosomes as transdermal drug delivery systems. Plain proniosomes comprising sorbitan monostearate, cholesterol, ethanol and a small quantity of water were initially prepared. Subsequently, proniosomes containing lecithin or skin penetration enhancers were prepared and evaluated for transdermal delivery of nisoldipine. The plain proniosomes significantly enhanced the transdermal flux of nisoldipine to reach 12.18μgcm−2h−1 compared with a saturated aqueous drug solution which delivered the drug at a rate of 0.46μgcm−2h−1. Incorporation of lecithin into such proniosomes increased the drug flux to reach a value of 28.51μgcm−2h−1. This increase can be attributed to the penetration enhancing effect of lecithin fatty acid components. Replacing lecithin oleic acid (OA) produced proniosomes of comparable efficacy to the lecithin containing system. The transdermal drug flux increased further after incorporation of propylene glycol into the OA based proniosomes. Similarly, incorporation of isopropyl myristate into plain proniosomes increased drug flux. The study introduced enhanced proniosomes as a promising transdermal delivery carrier and highlighted the role of penetration enhancing mechanisms in enhanced proniosomal skin delivery. The study opened the way for another line of optimisation of niosome proconcentrates.

Theoretical calculations of the pK a values of 1-aryl-4-propylpiperazine drugs in aqueous solution

Theoretical calculations were carried out to predict the aqueous-phase acidities of a series of drug 1-phenyl-4-propylpiperazine and its derivatives. The performances of the density functional theory(DFT) methods B3LYP and B3P86, solvation models[the polarized continuum model(PCM) and the conductor-like polarized continuum model(CPCM)], and the basis set effect were tested. A comparison between the theoretical and experimental pK a values for para-substituted 1-phenyl-4-propylpiperazines reveals that the accuracy of B3LYP is better than that of B3P86, and the basis set 6-31++G(d,p) and the CPCM model are suitable for calculating pK a values of the substituted 1-phenyl-4-propylpiperazine. For the investigated compounds, a reasonable agreement between the experimental and calculated pK a values was also observed.

Nanoformulation improves activity of the (pre)clinical anticancer ruthenium complex KP1019.

Ruthenium anticancer drugs belong to the most promising non-platinum anticancer metal compounds in clinical evaluation. However, although the clinical results are promising regarding both activity and very low adverse effects, the clinical application is currently hampered by the limited solubility and stability of the drug in aqueous solution. Here, we present a new nanoparticle formulation based on polymer-based micelles loaded with the anticancer lead ruthenium compound KP1019. Nanoprepared KP1019 was characterised by enhanced stability in aqueous solutions. Moreover, the nanoparticle formulation facilitated cellular accumulation of KP1019 (determined by ICP-MS measurements) resulting in significantly lowered IC50 values. With regard to the mode of action, increased cell cycle arrest in G2/M phase (PI-staining), DNA damage (Comet assay) as well as enhanced levels of apoptotic cell death (caspase 7 and PARP cleavage) were found in HCT116 cells treated with the new nanoformulation of KP1019. Summarizing, we present for the first time evidence that nanoformulation is a feasible strategy for improving the stability as well as activity of experimental anticancer ruthenium compounds.

Diclofenac Sodium Adsorption onto Montmorillonite: Adsorption Equilibrium Studies and Drug Release Kinetics

The aim of the present work was to investigate the role of montmorillonite clay as an oral drug delivery carrier for in vitro controlled release of anti-inflammatory drug diclofenac sodium (DS). For this purpose, the adsorption behaviour of DS onto the clay was studied as a function of pH of the aqueous drug solution, contact time, initial drug concentration and clay dosage. The clay-drug composites synthesized were subsequently characterized by X-ray diffraction studies, Fourier transform-infrared studies, differential scanning calorimetric analysis, thermogravimetric analysis, zeta-potential measurement, scanning electron microscopic and high-resolution transmission electron microscopic techniques. A drug loading of 497 mg/g was obtained in case of intercalated clay-drug composite. The in vitro drug release studies of the synthesized clay-drug composites in simulated gastric fluid (pH 1.2) showed no release, whereas a prolonged drug release profile was obtained for the intercalated clay-drug composite i...

PP-017 Dysphagia patients need semisolid oral dosage forms prepared by thickening liquids

BackgroundDysphagic patients are at risk of protein-energy malnutrition and dehydration as well as being incompliant to pharmacotherapy. Causes of dysphagia include neurological conditions (such as stroke, dementia, paraplegia/tetraplegia), otorhinolaryngology (ORL)...

Physicochemical properties of quercetin and rutin in aqueous solutions of decamethoxin antiseptic drug

The effect of a cationic surfactant, Decamethoxin, on the physicochemical properties of structurally related natural flavonoids, quercetin and rutin, was studied by spectrophotometry. The spectral and protolytic properties and the solubility of quercetin and rutin strongly depend on the Decamethoxin concentration in solution. The presence of Decamethoxin in the solution favors the tautomeric transition of the enol form of quercetin to the keto form.

Modulating topical drug delivery via skin pre-treatment with low-generation poly(amidoamine) dendrimers

The utilization of dendritic nanocarriers for enhanced skin delivery of active agents has been gaining growing popularity. However, the capability of dendrimers for skin delivery management has been under debate. As passive permeation of molecules is inversely related to the molecular weights, the purpose of this work was to investigate the extent to which the low-generation poly(amidoamine) (PAMAM) dendrimers enhance the skin penetration of a model active agent, salicylic acid. The aqueous solutions of amine-terminated (G2 and G3) PAMAM (1-10 mM) were employed to pre-treat the full-thickness pig skin, which was followed by the application of saturated aqueous drug solution. The results showed that G3 PAMAM did not exhibit an improvement of drug steady-state flux. In contrast, the skin pre-treatment by G2 PAMAM demonstrated a significant increase of drug flux up to ca. 2 folds in a dendrimer concentration-dependent manner. This study suggested the limited ability of low-generation PAMAM in modulating drug delivery to the skin.

Impact of Drug Administration Route on Drug Delivery and Distribution into the Lung: An Imaging Mass Spectrometry Approach

During the last decade, significant technological improvements in mass spectrometry have had a great impact on drug discovery. The development of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) has set a new frontier for the study of the distribution of endogenous and exogenous molecules present within a tissue. MALDI-IMS is a surface sampling technique that allows not only the detection of multiple analytes but also gives the spatial distribution of those analytes. Active compounds for pulmonary disease need an optimal and well-studied delivery into the lungs, in order to assure distribution with greater penetration into the peripheral or the alveolar region of the lung to maximize the therapeutic effects. IMS is very useful in the field of drug discovery, showing drug delivery and distribution in the body and organs. In this study, we present a comparison between two different ways of carrying out pulmonary drug administration: inhalation of a nebulized aerosol of aqueous drug solutions and intratracheal administration, which is much simpler, not expensive and commonly used during in vivo screening. Tiotropium bromide is a long-acting anticholinergic medicine used for maintenance treatment of chronic obstructive pulmonary disease. In the present work, tiotropium was administered by nebulization and by intratracheal instillation to guinea pigs at doses able to induce significant anti-bronchoconstrictive activity. Lung samples were dissected, frozen, cryosectioned and coated with matrix (α-hydroxy-cinnamic acid). IMS analyses were performed using a MALDI-LTQ-Orbitrap XL. Using this technique we were able to compare different distributions of the drug depending on the method of administration.

Enhanced cytotoxicity of optimized liposomal genistein via specific induction of apoptosis in breast, ovarian and prostate carcinomas

Clinical use of genistein against cancer is limited by its extremely low aqueous solubility, poor bioavailability and pharmacokinetics. Based on structural analogy with steroidal compounds, liposomal vehicle compositions were designed and optimized for maximum incorporation of genistein’s flavonoid structure. Model conventional and stealth liposomes of genistein (GenLip) – incorporating unsaturated phospholipids and cholesterol – have demonstrated enhanced drug solubilization (over 350-folds > aqueous drug solution), shelf-life stability, and extended release profile. Owing to effective cellular delivery, preservation of genistein’s antioxidant activity was confirmed through marked neutralization of peroxides via GenLip, in both quantitative and microscopic fluorescent-probe oxidation assays. Furthermore, significant broad-spectrum anticancer efficacy of GenLip, in murine and human cancer cell lines (p < 0.05–0.001), was achieved in a concentration and time-dependent manner – approx. 5–7 lower IC50 values versus all non-incorporated drug controls. Indicative of key pro-apoptotic activity, GenLip produced DNA laddering, with 1/3 of free drug solution content, and resulted in the highest induction level of P53-independent apoptotic pathway markers, compared to all treatments, in our assays (namely, mitochondrial polarization, and caspase-3/7 enzymes). Our proof-of-principle pharmaceutical design of genistein-loaded liposomes shows optimal loading capacity and physico-chemical properties, which improved cellular delivery and specific pro-apototic effectiveness of incorporated drug, against various cancers.

Development of novel elastic vesicle-based topical formulation of cetirizine dihydrochloride for treatment of atopic dermatitis.

Cetirizine is a piperazine-derived second-generation antihistaminic drug recommended for treatment of pruritus associated with atopic dermatitis. The present investigation encompasses development of a nanosized novel elastic vesicle-based topical formulation of cetirizine dihydrochloride using combination of Phospholipon® 90G and edge activators with an aim to have targeted peripheral H1 antihistaminic activity. The formulation was optimized with respect to phospholipid/drug/charge inducer ratio along with type and concentration of edge activator. The optimized formulation was found to be satisfactory with respect to stability, drug content, entrapment efficiency, pH, viscosity, vesicular size, spreadability, and morphological characteristics. The ex vivo permeation studies through mice skin were performed using Franz diffusion cell assembly. It was found that the mean cumulative percentage amount permeated in 8 h was almost twice (60.001 ± 0.332) as compared to conventional cream (33.268 ± 0.795) and aqueous solution of drug (32.616 ± 0.969), suggesting better penetration and permeation of cetirizine from the novel vesicular delivery system. Further, therapeutic efficacy of optimized formulation was assessed against oxazolone-induced atopic dermatitis in mice. It was observed that the developed formulation was highly efficacious in reducing the itching score (4.75 itches per 20 min) compared to conventional cream (9.75 itches per 20 min) with profound reduction in dermal eosinophil count and erythema score. To conclude, a novel vesicular, dermally safe, and nontoxic topical formulation of cetirizine was successfully developed and may be used to treat atopic dermatitis after clinical investigation.

Tuning the Dispersibility of Carbon Nanostructures from Organophilic to Hydrophilic: Towards the Preparation of New Multipurpose Carbon‐Based Hybrids

The hydroxyphenyl derivatives of carbon nanostructures (graphene and carbon nanotubes) can be easily transformed into highly organophilic or hydrophilic derivatives by using the ionic interactions between the phenolic groups and oleylamine or tetramethylammonium hydroxide, respectively. The products were finely dispersed in homo-polymers or block co-polymers to create homogeneous carbon-based nanocomposites and were used as nanocarriers for the dispersion and protection of strongly hydrophobic compounds, such as large aromatic chromophores or anticancer drugs in aqueous solutions.

Formulation and transport properties of tenofovir loaded liposomes through Caco-2 cell model

The aim was to investigate the potential of proliposomes to improve the permeability of tenofovir, anti-HIV, for oral delivery. Tenofovir was incorporated into phosphatidylcholine proliposomes and their absorption was determined in Caco-2 cell cultures grown on Transwell inserts using aqueous drug solutions as reference. Five batches of proliposomes were prepared with different stearylamine levels and characterized in terms of vesicular morphology, drug encapsulation efficiency (EEF), drug leakage, vesicular sizing and surface charges. Cytotoxicity of the reconstituted liposomes was evaluated by the MTT assay. The obtained results showed that increasing the incorporated percentage of stearylamine led to an increase in drug encapsulation, a slower drug leakage and larger liposomes formed. Compared to the drug solutions at corresponding concentrations, the proposed formulations showed a positive relationship (R2 = 0.9756) for the influence of increasing the stearylamine percentage on reduction of mitochondrial activity. Regarding the drug permeability, enhancements of apparent permeability by 16.5- and 5.2-folds were observed for proliposomes formulations with 5% and 15% stearylamine, respectively. A good correlation was observed between the Caco-2 and dialysis models that might indicate passive diffusion as well as paracellular transport as suggested mechanisms for drug absorption. Cationic proliposomes offered a potential formulation to improve the permeation of tenofovir.

Transfersomal lyophilized gel of buspirone HCl: formulation, evaluation and statistical optimization

Context: Buspirone HCl has very low oral bioavailability (4%) due to deactivation by extensive first pass effect. It also has very limited transdermal permeation due to its high hydrophilicity.Objective: The aim of this study was to increase the transdermal permeation of buspirone HCl utilizing a stable dosage form.Methods: Transfersomes were prepared using Tween-80 as a flexibility imparting agent to the vesicular walls. Oleic acid and/or ethanol, with different percentages, were utilized as a permeation enhancer. Formulations were characterized by analyzing particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro release and ex vivo drug permeation. Factorial design (32) was planned for the optimization of formulations using Design-Expert® software. Lyophilized transfersomal gel of the optimized formulation was prepared using hydroxypropyl methylcellulose (HPMC) K100, carboxymethyl cellulose or sodium alginate with or without mannitol as a cryoprotectant. Physical characterization of the transfersomes and the lyophilized gel were carried out using transmission and scanning electron microscopy, respectively.Results: The optimized formulation (T7), containing 35% oleic acid, had the highest desirability value (0.658) with high ex vivo drug flux (43.40 µg/h/cm2) through rat skin when compared with the aqueous drug solution and formula T1 (without oleic acid). The T7 transfersomal gel containing HPMC K100 (G2) had the highest desirability value (0.640) among the lyophilized gel formulations with decreased ex vivo drug flux (38.98 µg/h/cm2) in comparison with the original transfersomal formula (T7).Conclusions: Lyophilized transfersomal gel containing oleic acid was considered as a promising transdermal delivery system for hydrophilic drugs.

Studies on the Antagonistic Behavior Between Cyclophosphamide Hydrochloride and Aspirin with Human Serum Albumin: Time-Resolved Fluorescence Spectroscopy and Isothermal Titration Calorimetry

The interactions between cyclophosphamide hydrochloride (CYC) and aspirin (ASA) with human serum albumin (HSA) were investigated by measuring fluorescence anisotropy, poly-dispersity index, and time-resolved fluorescence. Also, isothermal titration calorimetry (ITC) was performed. The fluorescence spectra of the drugs exhibited an appreciable hypsochromic shift along with an enhancement in the fluorescence intensity. The gradual addition of HSA led to a marked increase in fluorescence anisotropy (r), and from this value it is argued that the drugs were located in a restricted environment of the protein. The binding constants for the ASA–HSA and CYC–HSA complexes were found to be 1.27 × 108 and 4.23 × 108 mol·L−1, respectively, as calculated from the relevant fluorescence data. The polydispersity index and size distribution of the protein–drug complex were measured at several concentrations of the drugs by the zeta potential technique, which confirmed the already obtained experimental results. From the analysis of the steady-state and time-resolved fluorescence quenching of the drugs in aqueous solutions in the presence of HSA, it was found that the quenching is static in nature. ITC experiments revealed that, in the absence of drugs, the dominant forces are electrostatic, whereas hydrophobic and weak electrostatic forces became significant in the presence of the drug. The primary binding pattern between the drugs and HSA was interpreted as a combined effect of hydrophobic association and electrostatic interactions.

Spherical agglomerates of pure drug nanoparticles for improved pulmonary delivery in dry powder inhalers

The aim of this study was to produce micron-sized spherical agglomerates of pure drug nanoparticles to achieve improved aerosol performance in dry powder inhalers (DPIs). Sodium cromoglicate was chosen as the model drug. Pure drug nanoparticles were prepared through a bottom-up particle formation process, liquid antisolvent precipitation, and then rapidly agglomerated into porous spherical microparticles by immediate (on-line) spray drying. Nonporous spherical drug microparticles with similar geometric size distribution were prepared by conventional spray drying of the aqueous drug solution, which together with the mechanically micronized drug particles were used as the control samples. The three samples were characterized by field emission scanning electron microscopy, laser diffraction, Brunauer–Emmett–Teller analysis, density measurement, powder X-ray diffraction, and in vitro aerosol deposition measurement with a multistage liquid impinger. It was found that drug nanoparticles with a diameter of ~100 nm were precipitated and agglomerated into highly porous spherical microparticles with a volume median diameter (D50 %) of 2.25 ± 0.08 μm and a specific surface area of 158.63 ± 3.27 m2/g. In vitro aerosol deposition studies showed the fine particle fraction of such spherical agglomerates of drug nanoparticles was increased by more than 50 % in comparison with the control samples, demonstrating significant improvements in aerosol performance. The results of this study indicated the potential of the combined particle engineering process of liquid antisolvent precipitation followed by immediate (on-line) spray drying in the development of novel DPI drug products with improved aerosol performance.

Liquid–Liquid Phase Separation in Highly Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs: Implications for Solubility Enhancing Formulations

Highly supersaturated aqueous drug solutions are often generated during drug testing and upon delivery to the patient. The phase behavior of such solutions appears complex and poorly understood, with the formation of colloidal drug aggregates often being reported. In this study, the phase behavior of eight hydrophobic poorly water-soluble drug molecules in highly supersaturated aqueous solutions was examined, and colloid formation was explained in terms of liquid–liquid phase separation (LLPS). A relationship was found between the concentration at which LLPS was observed and the theoretically predicted amorphous “solubility” value, where the latter was predicted based on the thermodynamic properties of the crystalline solid/supercooled liquid and solution activity coefficients. A phase diagram for the ritonavir–water system as a function of temperature was used to demonstrate that LLPS occurs in the metastable region of the phase diagram, and thus LLPS is a precursor to crystallization. Using an amorphous...

Photophysics of Silicon Phthalocyanines in Aqueous Media

Phthalocyanines have been used as photodynamic therapy (PDT) agents because of their uniquely favorable optical properties and high photostability. They have been shown to be highly successful for the treatment of cancer through efficient singlet-oxygen ((1)O(2)) production. However, due to their hydrophobic properties, the considerations of solubility and cellular location have made understanding their photophysics in vitro and in vivo difficult. Indeed, many quantitative assessments of PDT reagents are undertaken in purely organic solvents, presenting challenges for interpreting observations during practical application in vivo. With steady-state and time-resolved laser spectroscopy, we show that for axial ligated silicon phthalocyanines in aqueous media, both the water:lipophile ratio and the pH have drastic effects on their photophysics, and ultimately dictate their functionality as PDT drugs. We suggest that considering the presented photophysics for PDT drugs in aqueous solutions leads to guidelines for a next generation of even more potent PDT agents.

Densities and Speeds of Sound of l-Serine with Aqueous Solutions of Antibacterial Drugs at Different Temperatures

The volumetric and acoustic methods are used for investigating the interactions of l-serine with drugs ampicillin (AMP) and amoxicillin (AMX) as a function of temperature. Densities and speeds of sound of l-serine in (0.0009, 0.0018, 0.0028, and 0.0038) mol·kg–1 solutions of ampicillin and amoxicillin have been measured at T = (305.15, 310.15, and 315.15) K and atmospheric pressure. The density and speed of sound data have been used to determine apparent molar volume (Vϕ) and apparent molar adiabatic compressibility (Kϕ,s). The positive values of Vϕ and negative values of Kϕ,s indicate attractive interactions between l-serine and drug molecules. The pair interaction and triplet interaction coefficient for volumetric and acoustic data have also been calculated which suggest pairwise interactions between l-serine and drug molecules. The results have been discussed in terms of various interactions prevailing in aqueous solutions of amino acids and drugs.

Thiol-responsive block copolymer nanocarriers exhibiting tunable release with morphology changes

New thiol-responsive nanocarriers of amphiphilic block copolymers consisting of a pendent disulfide-labeled methacrylate polymer block (PHMssEt) and a hydrophilic poly(ethylene oxide) (PEO) block were reported. These well-controlled block copolymers were synthesized by atom transfer radical polymerization (ATRP) of a new pendent disulfide-functionalized methacrylate (HMssEt) in the presence of the PEO-Br macroinitiator. Due to its amphiphilic nature, the PEO-b-PHMssEt with narrow molecular weight distribution self-assembled in aqueous solution to form monomodal micellar aggregates with PHMssEt cores surrounded with hydrophilic PEO coronas. In response to thiols, the disulfide linkages were cleaved, and thus self-assembled micelles were either converted to core-crosslinked micelles or destabilized to further disintegrate, depending on the amount of added thiols. Such change in morphology led to tunable release of encapsulated model drugs in aqueous solutions.