In Vivo Assessment of Parenteral Formulations of Oligo(3-Hydroxybutyric Acid) Conjugates with the Model Compound Ibuprofen

Polymer-drug conjugates have gained significant attention as pro-drugs releasing an active substance as a result of enzymatic hydrolysis in physiological environment. In this study, a conjugate of 3-hydroxybutyric acid oligomers with a carboxylic acid group-bearing model drug (ibuprofen) was evaluated in vivo as a potential pro-drug for parenteral administration. Two different formulations, an oily solution and an o/w emulsion were prepared and administered intramuscularly (IM) to rabbits in a dose corresponding to 40 mg of ibuprofen/kilogramme. The concentration of ibuprofen in blood plasma was analysed by HPLC, following solid–phase extraction and using indometacin as internal standard (detection limit, 0.05 μg/ml). No significant differences in the pharmacokinetic parameters (Cmax, Tmax, AUC) were observed between the two tested formulations of the 3-hydroxybutyric acid conjugate. In comparison to the non-conjugated drug in oily solution, the relative bioavailability of ibuprofen conjugates from oily solution, and o/w emulsion was reduced to 17% and 10%, respectively. The 3-hydroxybutyric acid formulations released the active substance over a significantly extended period of time with ibuprofen still being detectable 24 h post-injection, whereas the free compound was almost completely eliminated as early as 6 h after administration. The conjugates remained in a muscle tissue for a prolonged time and can hence be considered as sustained release systems for carboxylic acid derivatives

Two-channel dansyl/tryptophan emitters with a cholic acid bridge as reporters for local hydrophobicity within supramolecular systems based on bile salts

The aim of the present work is to develop two-channel emitters to probe local hydrophobicity by means of fluorescence quenching within different biomimetic supramolecular environments. To achieve this goal, the dansyl (Dns) and tryptophan (Trp) fluorophores have been covalently attached to cholic acid (CA) in order to ensure simultaneous incorporation of the two emitting units into the same compartment. In principle, the two fluorophores of the synthesized Dns-CA-Trp probes could either exhibit an orthogonal behavior or display excited state interactions. The fluorescence spectra of 3 beta-Dns-CA-Trp showed a residual Trp emission band at ca. 350 nm and an enhanced Dns maximum in the 500-550 nm region. This reveals a partial intramolecular energy transfer, which is consistent with the Dns and Trp singlet energies. Thus, the two photoactive units are not orthogonal; nevertheless, 3 beta-Dns-CA-Trp seems appropriate as a two-channel reporter for the supramolecular systems of interest. Fluorescence quenching of 3 beta-Dns-CA-Trp by iodide (which remains essentially in bulk water) was examined within sodium cholate, sodium taurocholate, sodium deoxycholate and mixed micelles. Interestingly, a decrease in the emission intensity of the two bands was observed with increasing iodide concentrations. The most remarkable effect was observed for mixed micelles, where the quenching rate constants were one order of magnitude lower than in solution. As anticipated, the quenching efficiency by iodide decreased with increasing hydrophobicity of the microenvironment, a trend that can be correlated with the relative accessibility of the probe to the ionic quencher.Financial support from the Spanish Government (CTQ2012-38754-C03-03), Predoctoral FPU fellowship (AP2008-03295), and the Generalitat Valenciana (Prometeo Program) is gratefully acknowledged.Gómez Mendoza, M.; Marín García, ML.; Miranda Alonso, MÁ. (2014). Two-channel dansyl/tryptophan emitters with a cholic acid bridge as reporters for local hydrophobicity within supramolecular systems based on bile salts. Organic and Biomolecular Chemistry. 12(42):8499-8504. https://doi.org/10.1039/c4ob01394hS849985041242Vayá, I., Lhiaubet-Vallet, V., Jiménez, M. C., & Miranda, M. A. (2014). Photoactive assemblies of organic compounds and biomolecules: drug–protein supramolecular systems. Chem. Soc. Rev., 43(12), 4102-4122. doi:10.1039/c3cs60413fGomez-Mendoza, M., Marin, M. L., & Miranda, M. A. (2011). Dansyl Derivatives of Cholic Acid as Tools to Build Speciation Diagrams for Sodium Cholate Aggregation. The Journal of Physical Chemistry Letters, 2(7), 782-785. doi:10.1021/jz200178rGomez-Mendoza, M., Marin, M. L., & Miranda, M. A. (2012). Dansyl-Labeled Cholic Acid as a Tool To Build Speciation Diagrams for the Aggregation of Bile Acids. The Journal of Physical Chemistry B, 116(51), 14776-14780. doi:10.1021/jp308624hWaissbluth, O. L., Morales, M. C., & Bohne, C. (2006). Influence of Planarity and Size on Guest Binding with Sodium Cholate Aggregates. Photochemistry and Photobiology, 82(4), 1030. doi:10.1562/2006-02-14-ra-803Rinco, O., Kleinman, M. H., & Bohne, C. (2001). Reactivity of Benzophones in the Different Binding Sites of Sodium Cholate Aggregates. Langmuir, 17(19), 5781-5790. doi:10.1021/la010526cHofmann, A. F. (1999). The Continuing Importance of Bile Acids in Liver and Intestinal Disease. Archives of Internal Medicine, 159(22), 2647. doi:10.1001/archinte.159.22.2647Nuin, E., Gómez-Mendoza, M., Andreu, I., Marin, M. L., & Miranda, M. A. (2012). New Photoactive Compounds To Probe Cholic Acid and Cholesterol inside Mixed Micelles. Organic Letters, 15(2), 298-301. doi:10.1021/ol303201yHammad, M. ., & Müller, B. . (1998). Increasing drug solubility by means of bile salt–phosphatidylcholine-based mixed micelles. European Journal of Pharmaceutics and Biopharmaceutics, 46(3), 361-367. doi:10.1016/s0939-6411(98)00037-xHammad, M. ., & Müller, B. . (1998). Solubility and stability of tetrazepam in mixed micelles. European Journal of Pharmaceutical Sciences, 7(1), 49-55. doi:10.1016/s0928-0987(98)00006-2Hammad, M. (1998). Solubility and stability of clonazepam in mixed micelles. International Journal of Pharmaceutics, 169(1), 55-64. doi:10.1016/s0378-5173(98)00117-3Hendradi, E., Obata, Y., Isowa, K., Nagai, T., & Takayama, K. (2003). Effect of Mixed Micelle Formulations Including Terpenes on the Transdermal Delivery of Diclofenac. Biological & Pharmaceutical Bulletin, 26(12), 1739-1743. doi:10.1248/bpb.26.1739Parsaee, S., Sarbolouki, M. N., & Parnianpour, M. (2002). In-vitro release of diclofenac diethylammonium from lipid-based formulations. International Journal of Pharmaceutics, 241(1), 185-190. doi:10.1016/s0378-5173(02)00238-7Yu, J., Zhu, Y., Wang, L., Peng, M., Tong, S., Cao, X., … Xu, X. (2010). Enhancement of oral bioavailability of the poorly water-soluble drug silybin by sodium cholate/phospholipid-mixed micelles. Acta Pharmacologica Sinica, 31(6), 759-764. doi:10.1038/aps.2010.55Sznitowska, M., Klunder, M., & Placzek, M. (2008). Paclitaxel Solubility in Aqueous Dispersions and Mixed Micellar Solutions of Lecithin. CHEMICAL & PHARMACEUTICAL BULLETIN, 56(1), 70-74. doi:10.1248/cpb.56.70Nuin, E., Gomez-Mendoza, M., Marin, M. L., Andreu, I., & Miranda, M. A. (2013). Influence of Drug Encapsulation within Mixed Micelles on the Excited State Dynamics and Accessibility to Ionic Quenchers. The Journal of Physical Chemistry B, 117(32), 9327-9332. doi:10.1021/jp404353uCuquerella, M. C., Rohacova, J., Marin, M. L., & Miranda, M. A. (2010). Stereodifferentiation in fluorescence quenching within cholic acid aggregates. Chemical Communications, 46(27), 4965. doi:10.1039/c0cc00176gWu, J., Liu, W., Ge, J., Zhang, H., & Wang, P. (2011). New sensing mechanisms for design of fluorescent chemosensors emerging in recent years. Chemical Society Reviews, 40(7), 3483. doi:10.1039/c0cs00224kBronshtein, I., Afri, M., Weitman, H., Frimer, A. A., Smith, K. M., & Ehrenberg, B. (2004). Porphyrin Depth in Lipid Bilayers as Determined by Iodide and Parallax Fluorescence Quenching Methods and Its Effect on Photosensitizing Efficiency. Biophysical Journal, 87(2), 1155-1164. doi:10.1529/biophysj.104.041434Rohacova, J., Marin, M. L., Martínez-Romero, A., O’Connor, J.-E., Gomez-Lechon, M. J., Donato, M. T., … Miranda, M. A. (2009). Synthesis of new, UV-photoactive dansyl derivatives for flow cytometric studies on bile acid uptake. Organic & Biomolecular Chemistry, 7(23), 4973. doi:10.1039/b912134jFőrster, T. (1959). 10th Spiers Memorial Lecture. Transfer mechanisms of electronic excitation. Discuss. Faraday Soc., 27(0), 7-17. doi:10.1039/df9592700007Eaton, D. F. (1988). Reference materials for fluorescence measurement. Pure and Applied Chemistry, 60(7), 1107-1114. doi:10.1351/pac198860071107T. Förster , Modern Quantum Chemistry , Academic Press , New York , 196

Interactions between selected bile salts and Triton X-100 or sodium lauryl ether sulfate

<p>Abstract</p> <p>Background</p> <p>In order to develop colloidal drug carriers with desired properties, it is important to determine physico-chemical characteristics of these systems. Bile salt mixed micelles are extensively studied as novel drug delivery systems. The objective of the present investigation is to develop and characterize mixed micelles of nonionic (Triton X-100) or anionic (sodium lauryl ether sulfate) surfactant having oxyethylene groups in the polar head and following bile salts: cholate, deoxycholate and 7-oxodeoxycholate.</p> <p>Results</p> <p>The micellization behaviour of binary anionic-nonionic and anionic-anionic surfactant mixtures was investigated by conductivity and surface tension measurements. The results of the study have been analyzed using Clint's, Rubingh's, and Motomura's theories for mixed binary systems. The negative values of the interaction parameter indicate synergism between micelle building units. It was noticed that Triton X-100 and sodium lauryl ether sulfate generate the weakest synergistic interactions with sodium deoxycholate, while 7-oxodeoxycholate creates the strongest attractive interaction with investigated co-surfactants.</p> <p>Conclusion</p> <p>It was concluded that increased synergistic interactions can be attributed to the larger number of hydrophilic groups at α side of the bile salts. Additionally, 7-oxo group of 7-oxodeoxycholate enhance attractive interactions with selected co-surfactants more than 7-hydroxyl group of sodium cholate.</p

Human skin penetration of a copper tripeptide in vitro as a function of skin layer

Objective and designSkin retention and penetration by copper applied as glycyl-L-histidyl-L-lysine cuprate diacetate was evaluated in vitro in order to assess its potential for its transdermal delivery as an anti-inflammatory agent.Materials and methodsFlow-through diffusion cells with 1 cm(2) exposure area were used under infinite dose conditions. 0.68% aq. copper tripeptide as permeant was applied on isolated stratum corneum, heat-separated epidermis and dermatomed skin and receptor fluid collected over 48 h in 4 h intervals using inductively coupled plasma mass spectrometry to analyze for copper in tissues and receptor fluid.ResultsThe permeability coefficient of the compound through dermatomed skin was 2.43 ± 0.51 × 10(-4) cm/h; 136.2 ± 17.5 μg/cm(2) copper permeated 1 cm(2) of that tissue over 48 h, while 97 ± 6.6 μg/cm(2) were retained as depot.ConclusionsCopper as tripeptide was delivered in potentially therapeutically effective amounts for inflammatory disease

Human skin penetration of a copper tripeptide in vitro as a function of skin layer

We study a set of 28 GRB light-curves detected between 15 December 2002 and 9 June 2003 by the anti-coincidence shield of the spectrometer (SPI) of INTEGRAL. During this period it has detected 50 bursts, that have been confirmed by other instruments, with a time resolution of 50 ms. First, we derive the basic characteristics of the bursts: various duration measures, the count peak flux and the count fluence. Second, a sub-sample of 11 bursts with 12 individual, well-separated pulses is studied. We fit the pulse shape with a model by Kocevski et al. (2003) and find that the pulses are quite self-similar in shape. There is also a weak tendency for the pulses with steep power-law decays to be more asymmetric. Third, the variability of the complex light-curves is studied by analyzing their power-density-spectra (PDS) and their RMS variability.
The averaged PDS, of the whole sample, is a power-law with index of $1.60\pm0.05$ and a break between 1–2 Hz. Fourth, we also discuss the background and noise levels. We found that the background noise has a Gaussian distribution and its power is independent of frequency, i.e., it is white noise. However, it does not follow a Poisson statistic since on average the variance is ~1.6 larger than the mean. We discuss our results in context of the current theoretical picture in which GRBs are created in an anisotropic, highly relativistic outflow from collapsing massive stars. Finally, we note that the exact behaviour of the instrument is not yet known and therefore the above results should be treated as preliminary.

Solubilization of Drugs by Aqueous Lecithin Dispersions Intended for Parenteral Use

Egg lecithin is a complex mixture of phosphatides that consists mainly of phosphatidylcholine and phosphatidylethanolamine, combined with various amounts of other substances such as triglycerides and fatty acids [1]. [...

Superdisintegrants - excipients in dietary supplements in the form of tablets

Wśród środków spożywczych wyróżnia się suplementy diety, które produkowane są m. in. w postaci tabletek. Za jedną z najważniejszych substancji pomocniczych w takiej postaci uznaje się substancje rozsadzające, warunkujące rozpad tabletek w przewodzie pokarmowym i uwolnienie substancji aktywnych. Tradycyjne substancje rozsadzające stosowane w tabletkach to np. skrobia, hydrofilowe pochodne celulozy czy pektyny. Celem niniejszej pracy była charakterystyka substancji rozsadzających, tzw. superdezintegrantów, jak np. kroskarmeloza, krospowidon czy glikolan sodowy skrobi. Użycie superdezintegrantów pozwala uzyskać tabletki, które bardzo szybko rozpadają się w żołądku, uwalniając substancję aktywną w krótkim czasie. Mechanizm działania superdezintegrantów jest złożony i może polegać na pęcznieniu cząstek, odzyskiwaniu pierwotnego kształtu po sprasowaniu, egzotermicznych reakcjach zwilżania czy działaniu sił kapilarnych. W artykule, poza właściwościami stosowanych polimerów i mechanizmami ich działania omówiono także sposoby wprowadzania superdezintegrantów do tabletek (przed lub/i po granulacji). Uwzględniono również status prawny charakteryzowanych substancji pomocniczych na podstawie ustawy o bezpieczeństwie żywności i żywienia oraz wymagań obowiązującej Farmakopei.Amidst food products, there are dietary supplements, which are manufactured, among other things, in the form of tablets. Disintegrants in this form are considered to be one of the most important excipients since they determine the disintegration of tablets in the gastrointestinal tract and the release of the active substances. Traditional disintegrants used in tablets are, for example: starch, hydrophilic cellulose derivatives, or pectins. The objective of the review was to characterize the new generation of disintegrants, so called superdisintegrants, e.g. croscarmellose, crospovidone, and sodium starch glycolate. The utilization of superdisintegrants makes it possible to produce tablets that rapidly disintegrate in the stomach and release the active substance in a short time. The mechanism of action of superdisintegrants is complex and may include the swelling of particles, recovering the original shape by particles after they are compressed, exothermic wetting reactions, or capillary forces. In addition to the properties of the polymers used and the mechanisms of their action, the paper also discusses the methods of incorporating disintegrants into tablets (before or/and after the granulation process). The legal status of the substances being described is also taken into account based on the regulation on food and feed safety as well as on the requirements of the Pharmacopoeia in force

In Vitro Release of Indomethacin and Hydrocortisone from Suspensions and Self-Emulsifying Oils

Many drug substances exhibit low solubility in water, which results in their poor bioavailability. [...