Crystalline adduct of moxifloxacin with trans-cinnamic acid to reduce the aqueous solubility and dissolution rate for improved residence time in the lungs.
Abstract A crystalline adduct of the anti-tubercular drug, moxifloxacin and trans-cinnamic acid (1:1 molar ratio (MCA1:1)) was prepared to prolong the residence time of the drug in the lungs by reducing its solubility and dissolution rate. Whether the adduct is a salt or cocrystal has not been unequivocally determined. Equilibrium solubility and intrinsic dissolution rate measurements for the adduct (MCA1:1) in phosphate buffered saline (PBS, pH 7.4) revealed a significant decrease in the solubility of moxifloxacin (from 17.68 ± 0.85 mg mL-1 to 6.10 ± 0.05 mg mL-1) and intrinsic dis...
Source: European Journal of Pharmaceutical Sciences - June 17, 2019 Category: Drugs & Pharmacology Authors: Eedara BB, Tucker IG, Zujovic ZD, Rades T, Price JR, Das SC Tags: Eur J Pharm Sci Source Type: research

Exploration of long-acting implant formulations of hepatitis B drug entecavir.
Abstract Alternative formulations of entecavir (entecavir), a once daily oral hepatitis B antiretroviral, may improve treatment adherence by patients. We explored the use of biocompatible polymers to control entecavir dissolution in two formats suitable for subcutaneous implantation. Hot melt extrudates were prepared by extruding entecavir-polymer blends at specified weight ratios. Dip-coated tablets were prepared by compressing entecavir in a multi-tip tooling. Tablets were dip-coated in solutions of polymer and dried. In rodents, entecavir-polycaprolactone extrudates demonstrated>180 days of continuous drug...
Source: European Journal of Pharmaceutical Sciences - June 15, 2019 Category: Drugs & Pharmacology Authors: Henry SJ, Barrett SE, Forster SP, Teller RS, Yang Z, Li L, Mackey MA, Doto GJ, Ruth MP, Tsuchiya T, Klein LJ, Gindy ME Tags: Eur J Pharm Sci Source Type: research

Transdermal delivery of fluvastatin loaded nanoemulsion gel: Preparation, characterization and in vivo anti-osteoporosis activity.
The objective of present study was to develop hydrogel based nanoemulsion (NE) drug delivery system for transdermal delivery and evaluate its potential in in vivo anti-osteoporotic activity. NE was prepared using aqueous phase titration method and characterized for droplet size, zeta potential and morphology. It was then formulated into hydrogel based NE gel using carbopol 940 as gelling agent. NE gel was evaluated for pH, viscosity, in vitro/ex vivo permeation studies and in vivo anti-osteoporotic activity. The results indicated formation of spherical, nano sized globules of NE ranging from 11.17 ± 0.24 to 128....
Source: European Journal of Pharmaceutical Sciences - June 13, 2019 Category: Drugs & Pharmacology Authors: Kaur R, Ajitha M Tags: Eur J Pharm Sci Source Type: research

Novel insights into the chemistry of an old medicine: A general degradative pathway for penicillins from a piperacillin/tazobactam stability study.
Abstract Piperacillin is a broad spectrum beta-lactam antibiotic used in combination with tazobactam for hospital-related bacterial infections. The reconstituted solutions must respect the sub-visible and visible particles specifications. It was claimed that the reformulation containing EDTA/sodium citrate was able to control the formation of an insoluble impurity responsible for the formation of particulate matter observed using Ringer Lactate as diluent. The nature of the impurities formed during the degradative process of piperacillin/tazobactam combination has been herein investigated, by exploring the effect ...
Source: European Journal of Pharmaceutical Sciences - June 13, 2019 Category: Drugs & Pharmacology Authors: Viola A, Ferrazzano L, Martelli G, Cerisoli L, Ricci A, Tolomelli A, Cabri W Tags: Eur J Pharm Sci Source Type: research

Impact of phase separation morphology on release mechanism of amorphous solid dispersions.
Abstract Amorphous solid dispersions (ASDs) can phase separate in the gel phase during dissolution, lowering the chemical potential and thus the driving force for drug release. The purpose of this study is to explore the connection between amorphous phase separation in the hydrated ASD and its resulting release rate. Poorly soluble model compounds - indomethacin (IND) and ritonavir (RTV) - were formulated as ASDs using PVP as carrier. Rotating disk dissolution studies with varying drug loading levels of IND-PVP and RTV-PVP showed that the drug release was fastest at an intermediate drug loading level. This was in ...
Source: European Journal of Pharmaceutical Sciences - June 11, 2019 Category: Drugs & Pharmacology Authors: Han YR, Ma Y, Lee PI Tags: Eur J Pharm Sci Source Type: research

Immune network for viral hepatitis B: Topological representation.
iz IF Abstract The liver is a well-known immunotolerogenic environment, which provides the adequate setting for liver infectious pathogens persistence such as the hepatitis B virus (HBV). Consequently, HBV infection can derive in the development of chronic disease in a proportion of the patients. If this situation persists in time, chronic hepatitis B (CHB) would end in cirrhosis, hepatocellular carcinoma and eventually, the death of the patient. It is thought that this immunotolerogenic environment is the result of complex interactions between different elements of the immune system and the viral biology. Therefo...
Source: European Journal of Pharmaceutical Sciences - June 10, 2019 Category: Drugs & Pharmacology Authors: Asín-Prieto E, Parra-Guillen ZP, Mantilla JDG, Vandenbossche J, Stuyckens K, de Trixhe XW, Perez-Ruixo JJ, Troconiz IF Tags: Eur J Pharm Sci Source Type: research

Stabilizing excipients for engineered clopidogrel bisulfate procubosome derived in situ cubosomes for enhanced intestinal dissolution: Stability and bioavailability considerations.
Abstract Clopidogrel bisulfate (CB) is a golden antiplatelet treatment, yet its benefits are limited by its low bioavailability (
Source: European Journal of Pharmaceutical Sciences - June 9, 2019 Category: Drugs & Pharmacology Authors: El-Laithy HM, Badawi A, Abdelmalak NS, Elsayyad NME Tags: Eur J Pharm Sci Source Type: research

The effect of lysine substitutions in the biological activities of the scorpion venom peptide VmCT1.
In this study, we designed lysine-substituted VmCT1 analogs for verifying the influence of changes in the net positive charge on biological activities. The increase in the net positive charge caused by lysine substitutions in the hydrophilic portion, led to higher antimicrobial activity values (0.1-6.3 μmol L-1) than VmCT1 (0.8-50 μmol L-1) and higher activity against mammary cancer cells MCF-7 (6.3-12.5 μmol L-1) than VmCT1 (12.5 μmol L-1). Contrarily, when lysine-substitutions were made at the hydrophobic portion of the helical projection, the activity values decreased. However, the lysine-sub...
Source: European Journal of Pharmaceutical Sciences - June 7, 2019 Category: Drugs & Pharmacology Authors: Pedron CN, de Oliveira CS, da Silva AF, Andrade GP, da Silva Pinhal MA, Cerchiaro G, da Silva Junior PI, da Silva FD, Torres MT, Junior VXO Tags: Eur J Pharm Sci Source Type: research

Solid self-microemulsifying drug delivery system of Sophoraflavanone G: Prescription optimization and pharmacokinetic evaluation.
Abstract Sophoraflavanone G (SFG) is promising component in clinical treatment. The purpose of this study was to develop a drug delivery system in order to improve oral bioavailability of SFG. The optimum formulation of Self-microemulsifying Drug Delivery System with SFG (SFG-SMEDDS) was selected by the solubility test, self-microemulsifying grading test and ternary phase diagram test. The optimized formulation of SFG-S-SMEDDS was composed of Ethyl Oleate (38.5%, w/w), Cremophor RH40 (47.5%, w/w), PEG 400 (14.0%, w/w), and drug loading (20 mg/g). Mannitol as a solid absorbent was added to SFG-SMEDDS formulation ...
Source: European Journal of Pharmaceutical Sciences - June 5, 2019 Category: Drugs & Pharmacology Authors: Yang Z, Wang Y, Cheng J, Shan B, Wang Y, Wang R, Hou L Tags: Eur J Pharm Sci Source Type: research

A quality by design approach to develop topical creams via hot-melt extrusion technology.
In conclusion, this technology coupled with a design of experiments approach could be utilized to study how the extrusion process parameters could be modified to develop consistent topical creams with ideal product characteristics. PMID: 31173868 [PubMed - as supplied by publisher] (Source: European Journal of Pharmaceutical Sciences)
Source: European Journal of Pharmaceutical Sciences - June 4, 2019 Category: Drugs & Pharmacology Authors: Mendonsa NS, Pradhan A, Sharma P, Prado RMB, Murthy SN, Kundu S, Repka MA Tags: Eur J Pharm Sci Source Type: research

The inhibitory role of curcumin derivatives on AMPA receptor subunits and their effect on the gating biophysical properties.
Abstract Curcumin is a natural polyphenol that has a broad spectrum of therapeutic characters, including neuroprotective actions against various neurological diseases. However, the molecular mechanism behind its neuroprotective properties remains obscure. The current study investigated the neuroprotective properties of 7 different curcumin derivatives on the gating biophysical properties of AMPA receptors, specifically on the calcium-permeable homomeric GluA1 and calcium impermeable heteromeric GluA1/A2 subunits. Due to the association between excessive activation of AMPARs and neurotoxicity linked to numerous pat...
Source: European Journal of Pharmaceutical Sciences - June 4, 2019 Category: Drugs & Pharmacology Authors: Qneibi M, Hamed O, Fares O, Jaradat N, Natsheh AR, AbuHasan Q, Emwas N, Al-Kerm R, Al-Kerm R Tags: Eur J Pharm Sci Source Type: research

Single-dose escalation study of yogliptin in healthy Chinese volunteers.
CONCLUSION: Yogliptin was well tolerated in healthy subjects, with no dose-limiting toxicity observed in the range from 2.5 to 600 mg. Yogliptin inhibited plasma DPP-4 activity for 72 h at single doses of 25-200 mg and for 1 week at 400 mg, suggesting that once-weekly dosing of yogliptin is possible in type 2 diabetes patients. TRIAL REGISTRATION: ChiCTR-IIR-17010311 (Chictr.org). PMID: 31173870 [PubMed - as supplied by publisher] (Source: European Journal of Pharmaceutical Sciences)
Source: European Journal of Pharmaceutical Sciences - June 4, 2019 Category: Drugs & Pharmacology Authors: Gou ZP, Wang ZL, Liang XF, Zheng L, Wang Y, Feng P Tags: Eur J Pharm Sci Source Type: research

PAT-based batch statistical process control of a manufacturing process for a pharmaceutical ointment.
In this study, a process analytical technology (PAT)-based batch statistical process control (BSPC) model was developed for the laboratory-scale manufacturing process of a commercially available pharmaceutical ointment. The multivariate BSPC model was developed based on the in-line measured viscosity (viscometer), product temperature (viscometer), particle size distribution (PSD) (focused beam reflectance measurement (FBRM)) and active pharmaceutical ingredient (API) concentration (Raman spectroscopy) of four reference batches using a partial least squares (PLS) approach. From this in-line collected data, the characteristi...
Source: European Journal of Pharmaceutical Sciences - June 3, 2019 Category: Drugs & Pharmacology Authors: Bostijn N, Dhondt W, Vervaet C, De Beer T Tags: Eur J Pharm Sci Source Type: research

How can we improve the physical stability of co-amorphous system containing flutamide and bicalutamide? The case of ternary amorphous solid dispersions.
Abstract The article describes the preparation and characterization of binary mixtures of two antiandrogens used in prostate cancer treatment, i.e. flutamide (FL) and bicalutamide (BIC), as well as their ternary mixtures with either poly(methyl methacrylate-co-ethyl acrylate) (MMA/EA) or polyvinylpyrrolidone (PVP). The samples were converted into amorphous form to improve their water solubility and dissolution rate. Broadband dielectric spectroscopy and differential scanning calorimetry revealed that FL-BIC (65%) (w/w) does not tend to crystallize from the supercooled liquid state. We made the assumption that the ...
Source: European Journal of Pharmaceutical Sciences - June 3, 2019 Category: Drugs & Pharmacology Authors: Pacułt J, Rams-Baron M, Chmiel K, Jurkiewicz K, Antosik A, Szafraniec J, Kurek M, Jachowicz R, Paluch M Tags: Eur J Pharm Sci Source Type: research

Thermoplastic polyurethane as matrix forming excipient using direct and ultrasound-assisted compression.
llo I Abstract Thermoplastic polyurethanes (TPU) are block copolymers utilized in a wide variety of applications due to their superior characteristics as resistance, flexibility and biocompatibility. However, the use of TPU as a matrix tablet forming excipient is more limited. For the first time, matrix tablets based on TPU have been developed by direct compression and ultrasound-assisted compression (USAC) allowing a comparison between these two methods. TPU powder has been rheologically characterized according to SeDeM method, demonstrating the suitability of the polymer (Pearlbond™ 523) to be compressed. ...
Source: European Journal of Pharmaceutical Sciences - June 3, 2019 Category: Drugs & Pharmacology Authors: Casas M, Galdón E, Ojeda DJ, Caraballo I Tags: Eur J Pharm Sci Source Type: research

Inhibition of human cytochrome P450 2A6 by 7-hydroxycoumarin analogues: Analysis of the structure-activity relationship and isoform selectivity.
In this study, a series of 7-hydroxycoumarin and its structural analogues were collected to study their structure-activity relationship (SAR) and isoform selectivity for inhibiting CYP2A6. All tested coumarins except a C4 phenyl derivative (11) showed higher inhibitory activities for CYP2A6 over the other CYP isoforms, including CYP1A2, CYP2D6, CYP2E1, CYP3A4, CYP2C8, and CYP2C9. Of these coumarins, 6,7-dihydroxycoumarin (1) and 7,8-dihydroxycoumarin (9) were found to be potent inhibitors of CYP2A6 with IC50/Ki value of 0.39/0.25 and 4.61/3.02 μM, respectively, compared to methoxalen as positive control (IC50/Ki =...
Source: European Journal of Pharmaceutical Sciences - June 1, 2019 Category: Drugs & Pharmacology Authors: Qi X, Dou T, Wang Z, Wu J, Yang L, Zeng S, Deng M, Lü M, Liang S Tags: Eur J Pharm Sci Source Type: research

Prediction of the skin permeability of topical drugs using in silico and in vitro models.
h L, Pont M Abstract The main challenge of topically applied drugs is to overcome the skin barrier to reach the site of action at the concentration needed for efficacy. In the research of new topical drugs, design of molecules with optimized properties for skin penetration is a key factor and assays for its characterization are needed. A group of 20 representative topical molecules of clinical use were studied in two in silico models (Potts & Guy and Barratt), and an in vitro assay with artificial membrane (Skin-PAMPA). A subset of 9 drugs were also evaluated in the Franz cells assay, formulated in a solvent a...
Source: European Journal of Pharmaceutical Sciences - June 1, 2019 Category: Drugs & Pharmacology Authors: Alonso C, Carrer V, Espinosa S, Zanuy M, Córdoba M, Vidal B, Domínguez M, Godessart N, Coderch L, Pont M Tags: Eur J Pharm Sci Source Type: research

A population pharmacokinetic study to accelerate early phase clinical development for a novel drug, teriflunomide sodium, to treat systemic lupus erythematosus.
CONCLUSIONS: The pulsed EHC Pop PK model characterized the teriflunomide PK processes well in both healthy subjects and patients. Body weight, sex, and ABCG2 34G>A genotype were identified to significantly affect PK characteristics. The developed EHC Pop PK model exhibited the ability to predict PK profiles of teriflunomide in patients after long-term dosing and could be utilized to support phase II trial design. PMID: 31154006 [PubMed - as supplied by publisher] (Source: European Journal of Pharmaceutical Sciences)
Source: European Journal of Pharmaceutical Sciences - May 30, 2019 Category: Drugs & Pharmacology Authors: Yao X, Wu Y, Jiang J, Chen X, Liu D, Hu P Tags: Eur J Pharm Sci Source Type: research

Predicting pharmacokinetic behaviour of drug release from drug-eluting embolization beads using in vitro elution methods.
In this study, we describe two in vitro models capable of distinguishing between early phase and late phase drug release by mimicking in vivo features of each phase. First, a vascular flow system (VFS) was used to simulate the early phase by delivering DEB into a silicon vascular cast under high pulsatile flow. This yielded a burst release profile of drugs from DEB which related to the dose adjusted Cmax observed in pharmacokinetic plasma profiles from a preclinical swine model. Second, an open loop flow-through cell system was used to model late phase drug release by packing beads in a column with an ultra-low flow rate. ...
Source: European Journal of Pharmaceutical Sciences - May 29, 2019 Category: Drugs & Pharmacology Authors: Hagan A, Caine M, Press C, Macfarlane W, Phillips G, Lloyd AW, Czuczman P, Kilpatrick H, Bascal Z, Tang Y, Garcia P, Lewis AL Tags: Eur J Pharm Sci Source Type: research

Nanoparticulate delivery of irinotecan active metabolite (SN38) in murine colorectal carcinoma through conjugation to poly (2-ethyl 2-oxazoline)-b-poly (L-glutamic acid) double hydrophilic copolymer.
Abstract SN-38 is the active metabolite of irinotecan, an FDA-approved chemotherapeutic agent indicated for colorectal carcinoma, which would not be clinically applicable due to its very poorly soluble and hydrolytic degradation properties. To overcome these limitations, it was proposed to conjugate SN38 to residing carboxylic acid residues in poly (2-ethyl 2-oxazoline) block poly (L-glutamic acid), inducing nano-assembly in aqueous medium. Following a series of reactions including poly (2-ethyl oxazoline) macro-initiated ring opening polymerization of N-carboxyanhydride, deprotection of benzyl group and chemical ...
Source: European Journal of Pharmaceutical Sciences - May 25, 2019 Category: Drugs & Pharmacology Authors: Salmanpour M, Yousefi G, Samani SM, Mohammadi S, Anbardar MH, Tamaddon A Tags: Eur J Pharm Sci Source Type: research

Preclinical pharmacokinetics, disposition, and translational pharmacokinetic/pharmacodynamic modeling of savolitinib, a novel selective cMet inhibitor.
Abstract Savolitinib is a novel small-molecule selective cMet inhibitor. This work characterized its pharmacokinetics in preclinical phase, established the preclinical relationships between PK, cMet modulation and anti-tumor efficacy. In vitro and in vivo animal studies were performed for PK characterization. Savolitinib showed good absorption, moderate tissue distribution, low to intermediate clearance, and low accumulation. Hepatic oxidative metabolism followed by urinary and biliary excretions was the major elimination pathway. Based on preclinical PK data, human PK profiles were predicted using empirical metho...
Source: European Journal of Pharmaceutical Sciences - May 24, 2019 Category: Drugs & Pharmacology Authors: Gu Y, Sai Y, Wang J, Yu M, Wang G, Zhang L, Ren H, Fan S, Ren Y, Qing W, Su W Tags: Eur J Pharm Sci Source Type: research

Population pharmacokinetics and Monte Carlo simulations of sulbactam to optimize dosage regimens in patients with ventilator-associated pneumonia caused by Acinetobacter baumannii.
CONCLUSION: These findings indicate that high dosage combination regimens are required for the treatment of life-threatening infections in critically ill patients with VAP. PMID: 31132402 [PubMed - as supplied by publisher] (Source: European Journal of Pharmaceutical Sciences)
Source: European Journal of Pharmaceutical Sciences - May 24, 2019 Category: Drugs & Pharmacology Authors: Jaruratanasirikul S, Nitchot W, Wongpoowarak W, Samaeng M, Nawakitrangsan M Tags: Eur J Pharm Sci Source Type: research

Development of highly water-dispersible complexes between coenzyme Q10 and protein hydrolysates.
In this study, peptide mixtures derived from different proteins (casein, albumin, gelatin, lysozyme, zein and hemoglobin) were prepared and used as dispersants ofCoQ10. Most peptide mixtures, except for that derived from lysozyme, enhanced the water-dispersibility of CoQ10 by forming complexes with CoQ10. In particular, the apparent solubility of CoQ10complexed with the casein hydrolysate (Pepcas) was the highest. Pepcas was fractionated by ammonium sulfate precipitation and ultrafiltration to find the most effective peptides for enhancing water-dispersibility of CoQ10. The peptide fraction that had a relatively hydrophobi...
Source: European Journal of Pharmaceutical Sciences - May 23, 2019 Category: Drugs & Pharmacology Authors: Inada A, Oue T, Yamashita S, Yamasaki M, Oshima T, Matsuyama H Tags: Eur J Pharm Sci Source Type: research

PBPK modeling coupled with biorelevant dissolution to forecast the oral performance of amorphous solid dispersion formulations.
Abstract The aim of this research was to develop an in silico modeling and simulation approach to predict the oral performance of a poorly soluble drug candidate, T2CP, formulated as an amorphous solid dispersion and an amorphous powder. The dissolution and precipitation profiles of T2CP of the two amorphous formulations were evaluated in biorelevant media using USP 2 paddle apparatus. Three equations, the Noyes-Whitney equation for dissolution and separate equations describing nucleation and crystal growth, were fitted simultaneously to the in vitro profiles to estimate the dissolution and precipitation parameter...
Source: European Journal of Pharmaceutical Sciences - May 22, 2019 Category: Drugs & Pharmacology Authors: Kambayashi A, Kiyota T, Fujiwara M, Dressman JB Tags: Eur J Pharm Sci Source Type: research

Systematic evaluation of the impact of solid-state polymorphism on the bioavailability of thalidomide.
Abstract Thalidomide (TLD) is used to treat erythema nodosum leprosum (ENL), multiple myeloma, aphthous ulceration and wasting syndrome in HIV patients. The API can be found in two crystalline habits known as α-TLD and β-TLD. The saturation solubility (Cs) and the dissolution profiles under non-sink and sink conditions of both polymorphs were assessed. In addition, mini-capsules containing α-TLD or β-TLD without excipients were orally given (10 mg/kg) to Wistar rats. An intravenous (i.v.) dose was also administrated (5 mg/kg). The Cs values for α-TLD and β-TLD were not signific...
Source: European Journal of Pharmaceutical Sciences - May 22, 2019 Category: Drugs & Pharmacology Authors: de Oliveira GHO, do Nascimento SB, de Oliveira FM, Belo VS, de Alencar Danda LJ, Sobrinho JLS, Fialho SL, Bedor DCG, de Castro WV Tags: Eur J Pharm Sci Source Type: research

Cryo-milling using a spherical sugar: Contamination-free media milling technology.
Abstract Milling beads experience wear upon repeated use. And milling beads made of material that is safe when ingested have not yet been developed. The present report describes the development and characteristics of spherical d-mannitol (SDM) beads, which would be safe when ingested. The model drug phenytoin was dispersed in liquid nitrogen along with SDM and the materials were agitated at high speed. The effects of the amount of beads, agitation speed, and milling time on phenytoin particle size, yield, and bead fractures were investigated using a central composite experimental design. The diameter of milled phe...
Source: European Journal of Pharmaceutical Sciences - May 21, 2019 Category: Drugs & Pharmacology Authors: Uemoto Y, Kondo K, Niwa T Tags: Eur J Pharm Sci Source Type: research

The influence of core tablets rheology on the mechanical properties of press-coated tablets.
Abstract Press-coating (also called compression coating or dry coating) consists of a second compression of an outer layer of material over a preformed tablet core. Despite being old, this technology has returned to popularity due to its widespread use in preparation of chronotherapeutic dosage forms. The literature available on press-coated tablets has mainly investigated drug release kinetics, while there is a lack of information about their mechanical properties. Here we study, for the first time, the effect of material properties and manufacturing parameters on the mechanical characteristics of press-coated ta...
Source: European Journal of Pharmaceutical Sciences - May 18, 2019 Category: Drugs & Pharmacology Authors: Ascani S, Berardi A, Bisharat L, Bonacucina G, Cespi M, Palmieri GF Tags: Eur J Pharm Sci Source Type: research

Digital light processing (DLP) 3D-printing technology and photoreactive polymers in fabrication of modified-release tablets.
In this study, we assessed the feasibility of using digital light processing (DLP) 3D printers (3DP) in fabrication of solid oral dosage forms. The DLP technology uses a digital micromirror device (DMD) that reflects and focuses ultraviolet (UV) light on the surfaces of photoreactive materials that polymerize in a layer-by-layer fashion. Using poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) dimethacrylate (PEGDMA) as photoreactive polymers and theophylline as a model drug, we deployed a DLP printer to fabricate tablets. After optimizing various printing parameters including UV intensity and exposure time...
Source: European Journal of Pharmaceutical Sciences - May 17, 2019 Category: Drugs & Pharmacology Authors: Kadry H, Wadnap S, Xu C, Ahsan F Tags: Eur J Pharm Sci Source Type: research

Use of prior knowledge and extrapolation in paediatric drug development: A case study with deferasirox.
Abstract The characterisation of pharmacokinetics, pharmacodynamics and dose-exposure-response relationships requires data arising from well-designed study protocols and a relatively large sample from the target patient population. Such a prerequisite is unrealistic for paediatric rare diseases, where the patient population is often vulnerable and very small. In such cases, different sources of data and knowledge need to be considered to ensure trial designs are truly informative and oncoming data can be analysed efficiently. Here, we use clinical trial simulations to assess the contribution of historical data for...
Source: European Journal of Pharmaceutical Sciences - May 17, 2019 Category: Drugs & Pharmacology Authors: Borella E, Oosterholt S, Magni P, Pasqua OD Tags: Eur J Pharm Sci Source Type: research

Microdosed midazolam for the determination of cytochrome P450 3A activity: Development and clinical evaluation of a buccal film.
, Huwyler J Abstract Cytochrome P450 3A (CYP3A) isozymes metabolize about 50% of all marketed drugs. Their activity can be modulated up to 400-fold, which has great impact on individual dose requirements for CYP3A substrates. The activity of CYP3A can be monitored using the CYP3A substrate midazolam. To avoid pharmacological midazolam effects during phenotyping, a microdosing approach is preferred. However, the preparation of microdosed dosage forms remains a challenge. Fast dissolving buccal films are therefore proposed to facilitate this task. It was the aim of the present study to clinically evaluate a novel bu...
Source: European Journal of Pharmaceutical Sciences - May 15, 2019 Category: Drugs & Pharmacology Authors: Kiene K, Hayasi N, Burhenne J, Uchitomi R, Sünderhauf C, Schmid Y, Haschke M, Haefeli WE, Krähenbühl S, Mikus G, Inada H, Huwyler J Tags: Eur J Pharm Sci Source Type: research

Studying structural and local dynamics in model H-bonded active ingredient - Curcumin in the supercooled and glassy states at various thermodynamic conditions.
Abstract Different experimental techniques were applied to study thermal and structural properties, strength of H-bonds, possible keto-enol tautomerism and molecular dynamics at various thermodynamic conditions in the H-bonded active substance, curcumin (CRM). Dielectric measurements revealed dynamical features of examined compound that are uncharacteristic for the associated systems. This includes enormously large pressure coefficient of the glass transition temperature and prominent drop of the fragility with compression. Simultaneously, the shape of α-process slightly broadened at elevated pressures. Infr...
Source: European Journal of Pharmaceutical Sciences - May 10, 2019 Category: Drugs & Pharmacology Authors: Minecka A, Kamińska E, Heczko D, Jurkiewicz K, Wolnica K, Dulski M, Hachuła B, Pisarski W, Tarnacka M, Talik A, Kamiński K, Paluch M Tags: Eur J Pharm Sci Source Type: research

Er:YAG fractional laser ablation for cutaneous co-delivery of pentoxifylline and d- α-tocopherol succinate: A new approach for topical treatment of radiation-induced skin fibrosis.
The objective of this study was to investigate the feasibility of using Er:YAG fractional laser ablation to enable simultaneous cutaneous delivery of pentoxifylline and D- α -tocopherol succinate from poly(lactide-co-glycolide) microparticles prepared using the freeze-fracture technique. In vitro release experiments demonstrated the different release profiles of the two molecules, which were influenced by their very different lipophilicities and aqueous solubilities. Experiments were then performed to investigate the effect of laser fluence on pore depth and so determine the pore volume available to host the topicall...
Source: European Journal of Pharmaceutical Sciences - May 9, 2019 Category: Drugs & Pharmacology Authors: Gou S, Del Rio-Sancho S, Singhal M, Laubach HJ, Kalia YN Tags: Eur J Pharm Sci Source Type: research

Curcumin ameliorates the targeted delivery of methotrexate intercalated montmorillonite clay to cancer cells.
Abstract Montmorillonite Clay (MMT) is aimed to develop as an orally administrable drug delivery vehicle with enhanced efficacy. Aiming to enhance the therapeutic index of methotrexate, curcumin is concomitantly used with methotrexate in the present study. Being folate antagonist in nature, methotrexate is internalized into cells by folate receptor (FR); which is over-expressed in certain human cancer cells such as cervical carcinoma cells (HeLa). Firstly, montmorillonite Clay (MMT) is organically modified (OMMT) with cetyl trimethyl ammonium bromide (CTAB) and used to intercalate curcumin and methotrexate separat...
Source: European Journal of Pharmaceutical Sciences - May 9, 2019 Category: Drugs & Pharmacology Authors: Kar S, Kundu B, Reis RL, Sarkar R, Nandy P, Basu R, Das S Tags: Eur J Pharm Sci Source Type: research

Pharmacokinetics of the SABRE agent 4,6-d2-nicotinamide and also nicotinamide in rats following oral and intravenous administration.
Abstract To prepare the way for using the isotopically labelled SABRE hyperpolarized 4,6-d2-nicotinamide as an MRI agent in humans we have performed an in-vivo study to measure its pharmacokinetics in the plasma of healthy rats after intravenous and oral administration. Male Han Wistar rats were dosed with either 4,6-d2-nicotinamide or the corresponding control, non-labelled nicotinamide, and plasma samples were obtained at eight time points for up to 24 h after administration. Pharmacokinetic parameters were determined from agent concentration-versus-time data for both 4,6-d2-nicotinamide and nicotinamide. 4,6-...
Source: European Journal of Pharmaceutical Sciences - May 8, 2019 Category: Drugs & Pharmacology Authors: Linnik IV, Rayner PJ, Stow RA, Duckett SB, Cheetham GMT Tags: Eur J Pharm Sci Source Type: research

Evaluation of miscibility and polymorphism of synthetic and natural lipids for nanostructured lipid carrier (NLC) formulations by Raman mapping and multivariate curve resolution (MCR).
Abstract Nanostructured lipid carriers (NLC) belong to youngest lipid-based nanocarrier class and they have gained increasing attention over the last ten years. NLCs are composed of a mixture of solid and liquid lipids, which solubilizes the active pharmaceutical ingredient, stabilized by a surfactant. The miscibility of the lipid excipients and structural changes (polymorphism) play an important role in the stability of the formulation and are not easily predicted in the early pharmaceutical development. Even when the excipients are macroscopically miscible, microscopic heterogeneities can result in phase separat...
Source: European Journal of Pharmaceutical Sciences - May 6, 2019 Category: Drugs & Pharmacology Authors: Mitsutake H, Ribeiro LNM, Rodrigues da Silva GH, Castro SR, de Paula E, Poppi RJ, Breitkreitz MC Tags: Eur J Pharm Sci Source Type: research

Nanostructured clay particles supplement orlistat action in inhibiting lipid digestion: An in vitro evaluation for the treatment of obesity.
In this study, nanostructured clay (NSC) particles, fabricated by spray drying delaminated dispersions technologies that regulate energy uptake, to curb the rising trend in obesity statistics. In this study, nanostructured clay (NSC) particles, fabricated by spray drying delaminated dispersions of commercial clay platelets (Veegum® HS and LAPONITE® XLG), were delivered as complimentary, bioactive excipients with the potent lipase inhibitor, orlistat, for the inhibition of fat (lipid) hydrolysis. Simulated intestinal lipolysis studies were performed by observing changes in free fatty acid concentration and revealed ...
Source: European Journal of Pharmaceutical Sciences - May 5, 2019 Category: Drugs & Pharmacology Authors: Joyce P, Dening TJ, Meola TR, Gustafsson H, Kovalainen M, Prestidge CA Tags: Eur J Pharm Sci Source Type: research

Monitoring microsphere coating processes using PAT tools in a bench scale fluid bed.
Abstract Among the factors that influence adherence to medication within the pediatric population, taste/irritation has been identified as a critical barrier to patient compliance. With the goal of improving compliance, microspheres (matrix systems within which the drug is dispersed) can be coated with a reverse enteric polymer that will prevent the release of the drug in the oral cavity while maintaining an immediate release once the drug product reaches the stomach, thereby achieving a taste neutral profile. In this work, the in-line performance of three process analytical technology (PAT) tools is evaluated in ...
Source: European Journal of Pharmaceutical Sciences - May 5, 2019 Category: Drugs & Pharmacology Authors: Silva BS, Colbert MJ, Santangelo M, Bartlett JA, Lapointe-Garant PP, Simard JS, Gosselin R Tags: Eur J Pharm Sci Source Type: research

Simultaneously predict pharmacokinetic interaction of rifampicin with oral versus intravenous substrates of cytochrome P450 3A/P ‑glycoprotein to healthy human using a semi-physiologically based pharmacokinetic model involving both enzyme and transporter turnover.
Simultaneously predict pharmacokinetic interaction of rifampicin with oral versus intravenous substrates of cytochrome P450 3A/P‑glycoprotein to healthy human using a semi-physiologically based pharmacokinetic model involving both enzyme and transporter turnover. Eur J Pharm Sci. 2019 Apr 29;: Authors: Qian CQ, Zhao KJ, Chen Y, Liu L, Liu XD Abstract Several reports demonstrated that rifampicin affected pharmacokinetics of victim drugs following oral more than intravenous administration. We aimed to establish a semi-physiologically based pharmacokinetic (semi-PBPK) model involving both enzyme and tr...
Source: European Journal of Pharmaceutical Sciences - April 29, 2019 Category: Drugs & Pharmacology Authors: Qian CQ, Zhao KJ, Chen Y, Liu L, Liu XD Tags: Eur J Pharm Sci Source Type: research

Selective redox-responsive theragnosis nanocarrier for breast tumor cells mediated by MnO2/fluorescent carbon nanogel.
Abstract A redox-responsive fluorescent carbon nanogel (FCN) was designed as a bioimaging probe for targeted drug delivery to cancer cells. FCN was synthesized by the carbonization of disulfide cross-linked hyaluronic acid in the fluorescence "on" mode, followed by the attachment of manganese oxide (MnO2) nanosheets for fluorescence quenching (fluorescence "off"). We hypothesized that the fluorescence intensity of paclitaxel (PTX)-MnO2/FCN would suddenly increase (fluorescence "on") in the presence of a high level of glutathione (GSH) in cancer cells, owing to the reduction of MnO2 to...
Source: European Journal of Pharmaceutical Sciences - April 29, 2019 Category: Drugs & Pharmacology Authors: Choi CA, Ryplida B, In I, Park SY Tags: Eur J Pharm Sci Source Type: research

Pharmacophore based approach to screen and evaluate novel Mycobacterium cell division inhibitors targeting FtsZ - A modelling and experimental study.
This study employs the use of pharmacophore models derived from two different datasets based on Mtb-FtsZ GTPase inhibition and whole cell antibacterial activity, to virtually screen and shortlist novel compounds from In-house small molecule library as Mtb-FtsZ inhibitors and evaluate their in-vitro and ex-vivo activity. The results revealed Piperine (IC50 = 21.2 ± 0.7 μM), 4-Bromo di-methoxy coumarin (IC50 = 13.0 ± 1.6 μM) and Di-ethyl amino methyl coumarin (IC50 = 19.4 ± 1.1) as potent Mtb-FtsZ GTPase inhibitors which showed considerable antibacterial activity (84.0...
Source: European Journal of Pharmaceutical Sciences - April 26, 2019 Category: Drugs & Pharmacology Authors: Mitra K, Chadha A, Doble M Tags: Eur J Pharm Sci Source Type: research

Treatment of metastatic lung cancer via inhalation administration of curcumin composite particles based on mesoporous silica.
Abstract Curcumin attracted attention due to its promising anti-cancer properties and safety performance. However, its poor aqueous solubility and low bioavailability have to be overcome before it goes into clinic use. Here, porous composite particles are prepared by loading curcumin into mesoporous material SBA-15, and its therapeutic effect on lung cancer via inhalation administration have also been evaluated. The inclusion of curcumin in host material SBA-15 was confirmed by the reduced surface area and pore diameter of the composite material, and the aerodynamic performance of the composite material was invest...
Source: European Journal of Pharmaceutical Sciences - April 26, 2019 Category: Drugs & Pharmacology Authors: Su W, Wei T, Lu M, Meng Z, Chen X, Jing J, Li J, Yao W, Zhu H, Fu T Tags: Eur J Pharm Sci Source Type: research

Influence of particle size and blender size on blending performance of bi-component granular mixing: A DEM and experimental study.
g; R Abstract The effect of particle size enlargement and blender geometry down-scaling on the blend uniformity (BU) was evaluated by Discrete Element Method (DEM) to predict the blending performance of a binary granular mixture. Three 10 kg blending experiments differentiated by the physical properties specifically particle size were performed as reference for DEM simulations. The segregation behavior observed during the diffusion blending was common for all blends, while the sample BU, i.e., standard deviation of active ingredient content % was different among the three blends reflecting segregation due to the...
Source: European Journal of Pharmaceutical Sciences - April 26, 2019 Category: Drugs & Pharmacology Authors: Tanabe S, Gopireddy SR, Minami H, Ando S, Urbanetz NA, Scherließ R Tags: Eur J Pharm Sci Source Type: research

Solubility and bioavailability enhancement study of lopinavir solid dispersion matrixed with a polymeric surfactant - Soluplus.
Abstract As a biopharmaceutical classification system Class IV drug, lopinavir (LPV) shows relatively poor water solubility and permeation in vivo. In the study, we developed novel solid dispersions (SD) of LPV to improve its bioavailability and to describe their overall behaviors. By employing solvent evaporation for a preliminary formulation screening, the SDs of LPV-polymer-sorbitan monolaurate (SBM, as the wetting agent) at 1:4:0.4 (w/w) dramatically enhanced the LPV dissolution in a non-sink medium, and then hot-melt extrusion (HME) was applied to improve the dissolution further. A hydrophilic polymer - Kolli...
Source: European Journal of Pharmaceutical Sciences - April 24, 2019 Category: Drugs & Pharmacology Authors: Zi P, Zhang C, Ju C, Su Z, Bao Y, Gao J, Sun J, Lu J, Zhang C Tags: Eur J Pharm Sci Source Type: research

Multi-targeted anti-leukemic drug design with the incorporation of silicon into Nelarabine: How silicon increases bioactivity.
In this study, we evaluated the U.S Food and Drug Administration (FDA) approved ALL drugs according to their physicochemical and pharmaceutical properties, and Nelarabine was found to have the highest bioactivity score. Using the key strategy of bioisosterism commonly accepted by medicinal chemists, we investigated in silico ADME properties, drug-likeness, and biological activity of new designed twenty-four compounds including Nelarabine. The results were evaluated in terms of two classifications: broad spectrum biological activity and filtering of five different drug likeness criteria of the literature including Lipinski'...
Source: European Journal of Pharmaceutical Sciences - April 24, 2019 Category: Drugs & Pharmacology Authors: Eryilmaz E Tags: Eur J Pharm Sci Source Type: research

Reactive oxygen species and near-infrared light dual-responsive indocyanine green-loaded nanohybrids for overcoming tumour multidrug resistance.
Abstract The nucleus is in charge of the metabolism and heredity of the cell, and genetic mutations are closely related with tumour multidrug resistance (MDR). Indocyanine green (ICG), the FDA-approved photosensitizer, is widely used for tumour photodynamic therapy (PDT) and photothermal therapy (PTT). Few studies have clarified the cellular distribution of ICG in MDR tumour cells. In the study, ICG distribution was detected in the whole tumour cells of MCF-7 and MCF-7/ADR, especially in the nucleus, which led us to question whether increasing cellular accumulation and nuclear distribution of ICG could be a potent...
Source: European Journal of Pharmaceutical Sciences - April 23, 2019 Category: Drugs & Pharmacology Authors: Wang M, Xiao Y, Li Y, Wu J, Li F, Ling D, Gao J Tags: Eur J Pharm Sci Source Type: research

Topical nanostructured lipid carriers/inorganic sunscreen combination for alleviation of all-trans retinoic acid-induced photosensitivity: Box-Behnken design optimization, in vitro and in vivo evaluation.
Abstract All-trans retinoic acid is a natural retinoid and the physiologically active metabolite of vitamin A. The aim of the present study is to develop and optimize a nanostructured lipid carrier formulation to enhance the photostability of all-trans retinoic acid and alleviate its skin photosensitivity. Box-Behnken design was used for optimizing dependent variables such as particle size, zeta potential and viscosity. The total lipid (%), liquid lipid (%) and total surfactant (%) were selected as independent variables. The optimized formulation was characterized by particle size of 151 nm, zeta potential of -3...
Source: European Journal of Pharmaceutical Sciences - April 22, 2019 Category: Drugs & Pharmacology Authors: Asfour MH, Kassem AA, Salama A Tags: Eur J Pharm Sci Source Type: research

Quantitative analysis for lipophilic drug transport through a model lipid membrane with membrane retention.
In this study, we developed a permeability assay for lipophilic drugs with poor water solubility using a freestanding lipid bilayer. The lipid bilayer was created within a UV cuvette, and the number of transported molecules through the bilayer was estimated by measuring the UV absorbance over time. We then measured the permeability of six tested compounds, and there was a significant difference in permeability between the Biopharmaceutics Classification System (BCS) class 2 and class 4 compounds. In addition, the fraction of molecules trapped in the lipid bilayer were estimated for each compound as well. As a result, the d...
Source: European Journal of Pharmaceutical Sciences - April 22, 2019 Category: Drugs & Pharmacology Authors: Lee Y, Choi SQ Tags: Eur J Pharm Sci Source Type: research

Use of inspiratory profiles from patients with chronic obstructive pulmonary disease (COPD) to investigate drug delivery uniformity and aerodynamic dose emission of indacaterol from a capsule based dry powder inhaler.
Abstract Most patients using dry powder inhalers (DPIs) are unable to achieve the inhalation parameters recommended for pharmacopoeial in-vitro dose emission testing. The dose emission characteristics of indacaterol Breezhaler (IB) have been measured using COPD patients' inhalation profiles (IPs) when using IB and replayed in-vitro using a breath simulator attached to an Andersen Cascade Impactor. The peak inhalation flow (PIF) of the profiles ranged from 28.3 to 87.8 L/min and inhaled volumes (Vin) from 0.7 to 3 L. The indacaterol total emitted doses (TED), fine particle dose (FPD) and mass median aerodynamic...
Source: European Journal of Pharmaceutical Sciences - April 18, 2019 Category: Drugs & Pharmacology Authors: Abadelah M, Chrystyn H, Larhrib H Tags: Eur J Pharm Sci Source Type: research

Effect of inner pH on peptide acylation within PLGA microspheres.
Abstract Polymer degradation within the controlled-release depots comprising of lactide and glycolide (PLGA) forms an acidic microenvironment, in which severe acylation of the peptide by the polymer degradation products takes place. The aim of this study was to make out the role of the inner μpH on peptide acylation within the microspheres and how could it influence the reaction. The effects of pH on the acylation reaction within microspheres were composed of two aspects. Firstly, the inherent effect of pH on the acylation reaction itself was figured out: with the pH environment going up from acid to neutral, a...
Source: European Journal of Pharmaceutical Sciences - April 16, 2019 Category: Drugs & Pharmacology Authors: Liu J, Xu Y, Wang Y, Ren H, Meng Z, Liu K, Liu Z, Huang H, Li X Tags: Eur J Pharm Sci Source Type: research

Aryl quinolinyl hydrazone derivatives as anti-inflammatory agents that inhibit TLR4 activation in the macrophages.
Abstract A series of aryl 7-chloroquinolinyl hydrazone derivatives (3a-u) have been synthesized in 55-76% yield using simple reaction condition. The synthesized compounds were evaluated for their anti-inflammatory activities based on their ability to inhibit pro-inflammatory cytokine secretion from the macrophages after stimulation with lipopolysaccharide (LPS). Three compounds appeared as promising anti-inflammatory agents. The mechanism of inflammatory activity of the potent compound 3e was further investigated using a series of biochemical, molecular and microscopic techniques. Further structure activity relati...
Source: European Journal of Pharmaceutical Sciences - April 16, 2019 Category: Drugs & Pharmacology Authors: Debnath U, Mukherjee S, Joardar N, Sinha Babu SP, Jana K, Misra AK Tags: Eur J Pharm Sci Source Type: research