-
Journal of Controlled Release :... Sep 2014Lipid nanoemulsions and -suspensions are being intensively investigated as carriers for poorly water soluble drugs. The question on where model compounds or probes are...
Lipid nanoemulsions and -suspensions are being intensively investigated as carriers for poorly water soluble drugs. The question on where model compounds or probes are localized within the dispersions has been the subject of several studies. However, only little data exists for pharmaceutically relevant molecules in dispersions composed of pharmaceutically relevant excipients. In this work, the localization of drugs and drug-like substances was studied in lipid nanoemulsions and -suspensions. Conclusions about the drug localization were drawn from the relations between lipid mass, specific particle surface area and drug load in the dispersions. Additionally, the achievable drug loads of the liquid and the solid lipid particles were compared. Nanoemulsions and -suspensions comprised trimyristin as lipid matrix and poloxamer 188 as emulsifier and were prepared with different well-defined particle sizes. These pre-formed dispersions were passively loaded with either amphotericin B, curcumin, dibucaine, fenofibrate, mefenamic acid, propofol, or a porphyrin derivative. The physico-chemical properties of the particles were characterized; drug load and lipid content were quantified by UV spectroscopy and high performance liquid chromatography, respectively. For all drugs the passive loading procedure was successful in both emulsions and suspensions. Solid particles accommodate drug molecules preferably at the particle surface. Liquid particles can accommodate drugs at the particle surface as well as in the core; the distribution between the two sites is drug specific. It is also drug specific whether solid or liquid particles yield higher drug loads. As a general rule, smaller particles led to higher drug loads than larger ones. Propofol and the porphyrin derivative displayed eutectic interaction with the lipid and crystal growth after loading, respectively.
Topics: 1-Octanol; Amphotericin B; Chemistry, Pharmaceutical; Curcumin; Dibucaine; Drug Carriers; Emulsifying Agents; Emulsions; Fenofibrate; Mefenamic Acid; Nanoparticles; Particle Size; Poloxamer; Porphyrins; Propofol; Solubility; Triglycerides; Water
PubMed: 24933601
DOI: 10.1016/j.jconrel.2014.06.007 -
European Journal of Pharmaceutical... May 2018The development of methods to increase the bioavailability of drugs is of great interest, especially for those which are poorly soluble or permeable. One of the... (Comparative Study)
Comparative Study
The development of methods to increase the bioavailability of drugs is of great interest, especially for those which are poorly soluble or permeable. One of the strategies to enhance the solubility (which in turn has the potential of increase bioavailability) of drugs is the use of additives in the formulation process, so that the drug can stay supersaturated in biological fluids for a period of time long enough to allow absorption. The use of polymers as pharmaceutical excipients in order to stabilize the supersaturation of drugs is common practice. In this work, the ability of different polymers of vinylpyrrolidone (K-12, K-17, K-25, K-29/32, K-90) and a copolymer of vinylpyrrolidone and vinylacetate (S-630) have been tested for their impact on the supersaturation of drugs. Sixteen drugs of different chemical nature have been selected, and analyzed using the Cheqsol method. The results of the drug alone, and of physical mixtures with the different polymers at several polymer:drug ratios have been compared in terms of supersaturation extent and duration. It has been observed that acidic compounds displayed enhanced solubility in different ways: sometimes the supersaturated state of the drug is maintained for a long time, due to the precipitation of an amorphous solid, as determined by X-ray diffraction studies; on other occasions supersaturation increases but only for a short time, compared to the drug alone, and then the drug precipitates to a crystalline form. Only a few basic drugs displayed enhanced solubility in the presence of PVP polymers, in contrast to acidic compounds.
Topics: Crystallography, X-Ray; Drug Compounding; Drug Liberation; Excipients; Hydrogen-Ion Concentration; Kinetics; Models, Chemical; Pharmaceutical Preparations; Povidone; Powder Diffraction; Solubility; Technology, Pharmaceutical
PubMed: 29481859
DOI: 10.1016/j.ejps.2018.02.025 -
Contact Dermatitis Jun 2021
Topics: Adult; Austria; Dermatitis, Allergic Contact; Drug Combinations; Female; Germany; Humans; Male; Middle Aged; Patch Tests; Switzerland; para-Aminobenzoates
PubMed: 33400817
DOI: 10.1111/cod.13778 -
Journal of the European Academy of... Jul 2018
Topics: Anesthetics, Local; Calcium Channel Blockers; Dermatitis, Allergic Contact; Dibucaine; Diltiazem; Female; Fissure in Ano; Humans; Middle Aged; Patch Tests
PubMed: 29423962
DOI: 10.1111/jdv.14819 -
International Journal of Pharmaceutics Aug 2017Amongst other strategies for the formulation of poorly water-soluble drugs, solubilization of these drugs in lipid-based formulations is a promising option. Most...
Amongst other strategies for the formulation of poorly water-soluble drugs, solubilization of these drugs in lipid-based formulations is a promising option. Most screening methods for the identification of a suitable lipid-based formulation fail to elucidate the role interfacial effects play for drug solubility in disperse systems. In a novel screening approach called passive drug loading, different preformed lipid nanocarrier dispersions are incubated with drug powder. Afterwards, undissolved drug is filtered off and the amount of solubilized drug is determined. The aim of this study was to identify parameters for drug solubility in pure lipids as well as for drug loading to the lipid-water interface of lipid nanoparticles. Using passive loading, the solubility of eight poorly water-soluble drugs in seven lipid nanocarriers varying in particle size or lipid matrix was investigated. Drug solubility in the nanocarriers did not follow any apparent trend and different drugs dissolved best in different carriers. Drugs with a melting point below approximately 150°C displayed distinctly better solubility than higher melting drugs. Additionally, relating the specific lipid nanocarrier surface area to the drug solubility allowed drawing conclusions on the drug localization. Fenofibrate, dibucaine and, less distinctly also clotrimazole, which all melt below 150°C, were predominantly located in the lipid droplet core of the nanoparticles. In contrast, the five remaining drugs (betamethasone valerate, flufenamic acid, itraconazole, ketoconazole, mefenamic acid) were also located at the lipid-water interface to different, but substantial degrees. The ability to account for drug loading to the lipid-water interface is thus a major advantage of passive loading.
Topics: Chemistry, Pharmaceutical; Drug Carriers; Lipids; Nanoparticles; Particle Size; Solubility
PubMed: 28705617
DOI: 10.1016/j.ijpharm.2017.07.025 -
Pharmacoepidemiology and Drug Safety Nov 2016The aim of this study was to give an overview of the prevalence of contact allergy to active ingredients and excipients of topical medications across Europe.
PURPOSE
The aim of this study was to give an overview of the prevalence of contact allergy to active ingredients and excipients of topical medications across Europe.
METHODS
Retrospective analysis of data collected by the European Surveillance System on Contact Allergies (www.essca-dc.org) with substances applied to consecutively patch tested patients, 2009-2012, in 54 departments in 12 European countries.
RESULTS
In view of the varying composition of the baseline series used in the previously mentioned departments and countries, between 58 833 (lanolin alcohols) and 16 498 patients (sodium metabisulfite) were patch tested with the topical agents covered in this study. Among these, positive (allergic) reactions were most commonly observed to sodium metabisulfite (3.12% positive), followed by propolis (2.48%), Compositae mix (1.73%), lanolin alcohols (1.65%) and caine mix III (benzocaine, cinchocaine and tetracaine; 1.27%).
CONCLUSIONS
Several of the substances warrant routine screening for contact allergy, i.e. patch testing in a baseline series. However, in view of a vast number of other topical agents, additional patch testing with the suspect topical drug preparations (including natural remedies and cosmetics) is warranted. In the event of a positive test to the (pharmaceutical) product, single ingredients should be tested individually to precisely identify the hapten(s). Copyright © 2016 John Wiley & Sons, Ltd.
Topics: Administration, Topical; Adolescent; Adult; Aged; Allergens; Child; Child, Preschool; Dermatitis, Allergic Contact; Drug-Related Side Effects and Adverse Reactions; Europe; Excipients; Female; Humans; Male; Middle Aged; Patch Tests; Pharmaceutical Preparations; Prevalence; Retrospective Studies; Young Adult
PubMed: 27464585
DOI: 10.1002/pds.4064 -
The Journal of Physical Chemistry. B Jul 2015Side effects and excessive potentiation of drug efficacy caused by polypharmacy are becoming important social issues. The apparent partition coefficient of indomethacin...
Side effects and excessive potentiation of drug efficacy caused by polypharmacy are becoming important social issues. The apparent partition coefficient of indomethacin (log P'IND) increases in the presence of lidocaine, and this is used as a physicochemical model for investigating polypharmacy. We examined the changes in log P'IND caused by clinically used local anesthetics-lidocaine, tetracaine, mepivacaine, bupivacaine, and dibucaine-and by structurally similar basic drugs-procainamide, imipramine, and diltiazem. The quantitative structure-activity relationship study of log P'IND showed that the partition coefficient values (log PLA) and the structural entropic terms (ΔSobs, log f) of the additives affect log P'IND. These results indicate that the local anesthetics and structurally similar drugs function as phase-transfer catalysts, increasing the membrane permeability of indomethacin via heterogeneous intermolecular association. Therefore, we expect that the potency of indomethacin, an acidic nonsteroidal anti-inflammatory drug, will be increased by concurrent administration of the other drugs.
Topics: 1-Octanol; Anesthetics, Local; Anti-Inflammatory Agents; Entropy; Indomethacin; Lidocaine; Water
PubMed: 26121007
DOI: 10.1021/acs.jpcb.5b03984 -
PloS One 2014Butyrylcholinesterase deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium) in patients who have mutations in...
Butyrylcholinesterase deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium) in patients who have mutations in the BCHE gene. Here, we report a case of prolonged neuromuscular block after administration of suxamethonium leading to the discovery of a novel BCHE variant (c.695T>A, p.Val204Asp). Inhibition studies, kinetic analysis and molecular dynamics were undertaken to understand how this mutation disrupts the catalytic triad and determines a "silent" phenotype. Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine (BTC) and benzoylcholine, and values of dibucaine and fluoride numbers fit with heterozygous atypical silent genotype. Electrophoretic analysis of plasma BChE of the proband and his mother showed that patient has a reduced amount of tetrameric enzyme in plasma and that minor fast-moving BChE components: monomer, dimer, and monomer-albumin conjugate are missing. Kinetic analysis showed that the p.Val204Asp/p.Asp70Gly-p.Ala539Thr BChE displays a pure Michaelian behavior with BTC as the substrate. Both catalytic parameters Km = 265 µM for BTC, two times higher than that of the atypical enzyme, and a low Vmax are consistent with the absence of activity against suxamethonium. Molecular dynamic (MD) simulations showed that the overall effect of the mutation p.Val204Asp is disruption of hydrogen bonding between Gln223 and Glu441, leading Ser198 and His438 to move away from each other with subsequent disruption of the catalytic triad functionality regardless of the type of substrate. MD also showed that the enzyme volume is increased, suggesting a pre-denaturation state. This fits with the reduced concentration of p.Ala204Asp/p.Asp70Gly-p.Ala539Thr tetrameric enzyme in the plasma and non-detectable fast moving-bands on electrophoresis gels.
Topics: Alleles; Apnea; Base Sequence; Biocatalysis; Butyrylcholinesterase; DNA Mutational Analysis; Family Health; Female; Humans; Infant, Newborn; Isoquinolines; Kinetics; Male; Mivacurium; Molecular Dynamics Simulation; Mutation, Missense; Neuromuscular Depolarizing Agents; Pedigree; Succinylcholine
PubMed: 25054547
DOI: 10.1371/journal.pone.0101552 -
The West Virginia Medical Journal 2016Prolonged paralysis due to a quantitative or qualitative deficiency of pseudocholinesterase activity is an uncommon but known side effect of succinylcholine. We describe...
Prolonged paralysis due to a quantitative or qualitative deficiency of pseudocholinesterase activity is an uncommon but known side effect of succinylcholine. We describe a patient who experienced prolonged paralysis following administration of succinylcholine for general anesthesia and endotracheal intubation for an emergent cesarean section despite laboratory evidence of normal enzyme function. The patient required mechanical ventilation in the intensive care unit for several hours following surgery. The patient was extubated following return of full muscle strength and had a good outcome. The enzyme responsible for the metabolism of succinylcholine, pseudocholinesterase, was determined to be low in quantity in this patient but was functionally normal. This low level, by itself, was unlikely to be solely responsible for the prolonged paralysis. The patient likely had an abnormal pseudocholinesterase enzyme variant that is undetectable by standard laboratory tests.
Topics: Adult; Anesthesia, General; Anesthetics, Local; Butyrylcholinesterase; Cesarean Section; Dibucaine; Emergencies; Female; Humans; Intensive Care Units; Intubation, Intratracheal; Neuromuscular Depolarizing Agents; Obstetric Labor Complications; Paralysis; Pregnancy; Respiration, Artificial; Succinylcholine; Time Factors; Treatment Outcome
PubMed: 27025119
DOI: No ID Found -
Cutaneous and Ocular Toxicology 2015Topical medications are frequently neglected as the potential cause of systemic drug reactions. In this case report, a patient with a maculopapular eruption attributed...
Topical medications are frequently neglected as the potential cause of systemic drug reactions. In this case report, a patient with a maculopapular eruption attributed to a drug hypersensitivity reaction was submitted to skin patch tests in order to clarify the drug implicated. Incidentally, a positive reaction to cinchocaine was observed. With the ulterior confirmation of the application of an antihemorrhoidal ointment containing cinchocaine, which was omitted during the initial anamnesis, the diagnosis of systemic contact dermatitis to cinchocaine was made.
Topics: Dermatitis, Contact; Dibucaine; Female; Humans; Middle Aged; Patch Tests
PubMed: 25198408
DOI: 10.3109/15569527.2014.952375