SYNTHESIS AND FORMULATION OF IBUPROFEN PRO-DRUGS FOR ENHANCED TRANSDERMAL ABSORPTION

Objectives: The aim is to synthesize ibuprofen prodrugs that have more suitable physicochemical properties and formulate them into a liquid formulation for topical administration. The transdermal delivery (TDD) is one of the most attractive routes for drug administration as it eliminates the GIT absorption variable, improves patient compliance and also reduces drug plasma fluctuations. However, TDD only drugs with suitable physico-chemical properties can be absorbed. The oral administration of NSAIDs for a long time can cause gastric mucosal damage, which may result in ulceration and bleeding. Thus, the development of a TDD of NSAIDs is of great interest as it decreases GIT side effectsMethods: The synthesis of ibuprofen alkyl esters was carried out by esterification reactions with methanol, ethanol, propanol, butanol, pentanol and hexanol. The formulated samples were then subjected to stability studies according to ICH guidelines.Results: We have successfully synthesized and characterized various esters of ibuprofen. Moreover, ibuprofen butyl ester has been prepared as topical solutions. The formulated TDD was tested for stability according to ICH guidelines and the results showed no changes in the initial appearance during three months of study at room temperature & at 40 °C.Conclusion: The assay and pH were within the pharmacopeial limits during the period of the study. In conclusion, stable topical formulation of Ibuprofen esters was obtained.Â

Surface modulation of single-walled carbon nanotubes for selective bacterial cell agglutination

Background: Bacterial resistance to antibiotics is one of the biggest challenges facing medicine today. Anti-adhesive therapy, using inhibitors of bacterial adhesion to epithelial cells, one of the first stages of infection, is a promising approximation in this area. The size, shape, number of sugar and their placement are variables that have to be taken into account in order to develop multivalent systems able to inhibit the bacterial adhesion based on sugar-lectin interaction. Materials and methods: In the present work we report a modular approach for the synthesis of water-soluble 1D-carbon nanotube-sugar nanoconstructs, with the necessary flexibility to allow an efficient sugar-lectin interaction. The method is based on the reaction of aryl diazonium salts generated in situ from aniline-substituted mannose and lactose derivatives with single wall carbon nanotubes (SWCNTs) sidewalls. Results: Two hybrid nanosystems, I-II, exposing mannose or lactose and having a tetraethylene glycol spacer between the sugar and the nanotube sidewall were rapidly assembled and adequately characterized. The sweet nano-objects were then tested for their ability to agglutinate and selectively inhibit the growth of uropathogenic Escherichia coli. These studies have shown that nanosystem I, exposing mannose on the nanotube surface is able to agglutinate and to inhibit the bacterial growth unlike nano-objects II exposing lactose. Conclusion: The results reported constitute a proof of principle in using mannose-coated 1D-carbon nanotubes as antiadhesive drugs that compete for FimH binding and prevent the uropathogenic bacteria from adhering to the urothelial surface.Andalusian Government (FQM-313 to NK, BIO-026 to REW)Spanish Ministry of Economy and Competitiveness (CTQ2016-78580-C2-1-R to NK)University of Seville (V PLAN PROPIO to REW)European Regional Development Fund (FEDER

Nanotubos de carbono biocampatibles, síntesis y aplicaciones en biomedicina

Considerando todo lo comentado anteriormente, el planteamiento general de esta Tesis Doctoral ha consistido en la síntesis de nuevos sistemas nanométricos que emulen la estructura de la membrana celular. Teniendo en cuenta que de una manera esquemática una membrana celular puede definirse como una bicapa lipídica recubierta de hidratos de carbono, los modelos diseñados en esta Tesis Doctoral han ido encaminados hacia la construcción de este tipo de organizaciones supramoleculares, y su aplicación en procesos biológicos que implican carbohidratos. Para cumplirlos, se han planteados tres objetivos principales, que a su vez, se subdividen en varios objetivos parciales definidos, de manera que se pueden alcanzar de un modo rápido, eficiente y convergente. - El primer objetivo básico consiste en el uso de nanotubos de carbono como plataforma naométrica para la síntesis gliconanomateriales biocompatibles solubles en agua. - El segundo objetivo principal está encaminado hacia la síntesis de nuevos nanomateriales con una cavidad interna hidrófoba y su uso como nanovectores para el transporte inteligente de medicamentos. - El tercer y último objetivo, consiste en estudio de la autoorganización supramolecular de neoglicolípidos con el fin de sintetizar nuevos bionanomateriales. En el capítulo I, y dentro del primer objetivo básico, se ha planteado como objetivo parcial la funcionalización no covalente de nanotubos de carbono, empleando neoglicolípidos anfifílicos que poseen una parte hidrófoba portadora de un sustituyente aromático capaz de interaccionar mediante fuerzas de tipo apilamiento π-π con la superficie del nanotubo. Para la solubilización de nanotubos monocapa, se plantea el uso del pireno como sustituyente aromático por su conocida capacidad de interaccionar con el plano basal del sistema π del grafito con una magnitud relativamente elevada. Para la solubilización de los nanotubos multicapa se ha planteado como objetivo adicional desarrollar un anclaje aromático nuevo, complementario del pireno, derivado deltetrabenzo[a,c,g,i]fluoreno (Tbf), un compuesto cuya estructura recuerda a una mariposa con alas abiertas. Los agregados preparados serán solubles en agua, biocompatibles con una exposición multivalente de motivos glucídicos y cuya capacidad de reconocer biomoléculas de forma será determinada. El objetivo del tercer capítulo consiste en el desarrollo de una metodología de solubilización de nanotubos de carbono monocapa que aúna las ventajas de la funcionalización covalente y la no covalente mediante el mantenimiento de la integridad estructural de los nanotubos de carbono paralelmente a una elevada estabilidad. Para ello, se ha planteado el uso del neoglicolípidoIV, que tiene como parte lipídica un derivado diacetilénico, diseñado para aumentar la estabilidad de los agregados mediante una fotopolimerización posterior. Una vez comprobada la autorganización en semicilindro, semejante a la observada con el SDS, se llevara a cabo una etapa de fotopolimerización mediante una luz ultravioleta (254 nm), que conducira a la obtención de nanotubos de carbono rodeados de gliconanoanillos. En los agregados formados, cada molécula de lípido esta enlazada con dos de las moléculas adyacentes, generando así una red de polímeros lipídicos entrelazados, que confieren así la rigidez y estabilidad esperadas al entramado supramolecular. Los agregados obtenidos serán solubles en agua, de tamaño nanométrico, y cuya estructura tiene bastante semejanza con la membrana celular. Asimismo, los anillos con estructura de bicapa lipídica exponen un gran número de glicoligandos hacia la fase acuosa de manera similar al glicocálix, mientras que los nanotubos de carbono confieren estabilidad al entramado molecular de la misma manera que el citoesqueleto en la membrana celular. Es por ello, que una vez obtenidos se llevaran a cabo estudios de reconocimiento molecular con lectinas, y de agregación bacteriana como etapa previa al desarrollo de antibióticos de nueva generación. Uno de los objetivos fundamentales planteado en el capítulo IV, consiste en la síntesis de nuevos nanovectores que aúnen las ventajas estructurales de las nanopartículas utilizadas en la vectorización activa de medicamentos con una cavidad adicional interna capaz de hospedar, proteger, solubilizar en agua y transportar principio activos hidrófobos. Para alcanzar este objetivo y aprovechando que los anillos resultantes tras la polimerización de los agregados de glicolípidos alrededor de los nanotubos obtenidos en el capítulo III presentan una naturaleza compacta y rígida se llevará a cabo estudios dirigidos para extraerlos de los nanotubos y obtener así nuevos bionanomateriales, que se han denominado gliconanosomas (GNS). Estos nanomateriales están dotados de una cavidad interna hidrófoba cuyo tamaño depende del nanotubo utilizado como molde, y una superficie externa hidrófila debida a la cadena PEG y a la subunidad de carbohidrato. Aprovechando estas características estructurales idóneas para el transporte inteligente de medicamentos, se llevarán a cabo estudios de solubilización en agua y el transporte de moléculas de interés biológico. En el capítulo V, nos hemos propuesto dos objetivos concretos: el primero, consiste en desarrollar una nueva aproximación sintética modulable y convergente para la síntesis de una nueva serie de compuestos anfifílicos derivados de ácidos grasos diacetilénicos que presentan un anillo de triazol como puente de unión entre el fragmento glicosídico y la cadena lipídica. El segundo objetivo, consiste en el estudio de su capacidad de generar diversidad supramolecular mediante autoorganización, y su aplicación para la síntesis de sistemas nanométricos de interés. Concretamente y en un primer lugar, se estudiará la autoasociación de los anfífilos sintetizados para formar liposomas y su utilización como sensor colorimétrico para detectar lectinas y bacterias, así como vehículo para transportar antitumorales insoluble en agua. En un segundo lugar, se estudiará su capacidad para formar estructuras monodimensionales tubulares estabilizadas por diferentes fuerzas simultáneas, con especial énfasis en el aporte de la interacción por apilamiento π entre los anillos de triazol formados frente al enlace de hidrógeno entre las amidas. Finalmente, se estudiará la capacidad de los neoglicolípidos para formar hidrogeles, su caracterización, y su uso para la encapsulación y liberación controlada del antitumoral topotecan

RP-HPLC Method Development and Validation of Synthesized Codrug in Combination with Indomethacin, Paracetamol, and Famotidine

Background. Indomethacin is considered a potent nonsteroidal anti-inflammatory drug that could be combined with Paracetamol to have superior and synergist activity to manage pain and inflammation. To reduce the gastric side effect, they could be combined with Famotidine. Methodology. A codrug of Indomethacin and Paracetamol was synthesized and combined in solution with Famotidine. The quantification of the pharmaceutically active ingredients is pivotal in the development of pharmaceutical formulations. Therefore, a novel reverse-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated according to the International Council for Harmonization (ICH) Q2R1 guidelines. A reverse phase C18 column with a mobile phase acetonitrile: sodium acetate buffer 60 : 40 at a flow rate of 1.4 mL/min and pH 5 was utilized. Results. The developed method showed good separation of the four tested drugs with a linear range of 0.01–0.1 mg/mL (R2 > 0.99). The LODs for FAM, PAR, IND, and codrug were 3.076 × 10−9, 3.868 × 10−10, 1.066 × 10−9, and 4.402 × 10−9 mg/mL respectively. While the LOQs were 9.322 × 10−9, 1.172 × 10−10, 3.232 × 10−9, and 1.334 × 10−8 mg/mL, respectively. Furthermore, the method was precise, accurate, selective, and robust with values of relative standard deviation (RSD) less than 2%. Moreover, the developed method was applied to study the in vitro hydrolysis and conversion of codrug into Indomethacin and Paracetamol. Conclusion. The codrug of Indomethacin and Paracetamol was successfully synthesized for the first time. Moreover, the developed analytical method, to our knowledge, is the first of its kind to simultaneously quantify four solutions containing the following active ingredients of codrug, Indomethacin, Paracetamol, and Famotidine mixture with added pharmaceutical inactive ingredients in one HPLC run

Synthesis, Biological Activity, and Molecular Modeling Studies of Pyrazole and Triazole Derivatives as Selective COX-2 Inhibitors

Series of diaryl-based pyrazole and triazole derivatives were designed and synthesized in a facile synthetic approach in order to produce selective COX-2 inhibitor. These series of derivatives were synthesized by different reactions like Vilsmeier–Haack reaction and click reaction. In vitro COX-1 and COX-2 inhibition studies showed that five compounds were potent and selective inhibitors of the COX-2 isozyme with IC50 values in 0.551–0.002 μM range. In the diarylpyrazole derivatives, compound 4b showed the best inhibitory activity against COX-2 with IC50 = 0.017 μM as one of the N-aromatic rings was substituted with sulfonamide and the other aromatic ring was unsubstituted. However, when the N-aromatic ring was substituted with sulfonamide and the other aromatic ring was substituted with sulfone (compound 4d), best COX-2 selectivity was achieved (IC50 = 0.098 μM, SI = 54.847). In the diaryltriazole derivatives, compound 15a showed the best inhibitory activity in comparison to all synthesized compounds including the reference celecoxib with IC50 = 0.002 μM and SI = 162.5 as it could better fit the extra hydrophobic pocket which is present in the COX-2 enzyme. Moreover, the docking study supports the obtained SAR data and binding similarities and differences on both isozymes

Improved non-covalent biofunctionalization of multi-walled carbon nanotubes using carbohydrate amphiphiles with a butterfly-like polyaromatic tail

15 páginas, 8 figuras, 1 tabla, 3 esquemas.We have developed an efficient strategy for the non-covalent functionalization of multi-walled carbon nanotubes (MWCNTs) which allows a biomimetic presentation of carbohydrates on their surface by π-π stacking interactions. The strategy is based on the use of sugar-based amphiphiles functionalized with tetrabenzo[a,c,g,i]fluorene (Tbf), a polyaromatic compound with a topology that resembles a butterfly with open wings. The new carbohydrate-tethered Tbf amphiphiles have been synthesized in a straightforward manner using click chemistry. The reported method has been developed in order to improve the rather low ability of pyrene-based systems to exfoliate MWCNTs in water. By means of thermogravimetric analysis (TGA), ultraviolet (UV), infrared (IR), and fluorescence spectroscopies the interaction between MWCNTs and the Tbf group has been found to be stronger than those involving pyrene-based amphiphilic carbohydrates. The resulting aggregates with a multivalent sugar exposition on their surface are able to engage in specific ligand-lectin interactions similar to glycoconjugates on a cell membrane.This work was supported by the Ministerio de Ciencia e Innovación (grant No. CTQ2010-21755-CO2-00), the Junta de Andalucía (grant Nos. P06-FQM-01852 and P07-FQM-2774), the Centre National de la Recherche Scientifique (France) and the Consejo Superior de Investigaciones Científicas (Egide Picasso 09543XA and Projets Internationaux de Cooperation Scientifiques Program 2008-2010).Peer reviewe

Non-covalent functionalization of carbon nanotubes with glycolipids: glyconanomaterials with specific lectin-affinity

3 páginas, 3 figuras, 1 esquema.A strategy based on the utilization of neutral pyrene functionalized neoglycolipids I that interact with a CNT’s surface giving rise to biocompatible nanomaterials which are able to engage specific ligand-lectin interactions similar to glycoconjugates on the cell membrane is reported.Financial supports from the DGICyT (grant No. CTQ2006-15515-CO2-01 and CTQ2007-61185), the Junta de Andalucía (grant P06-FQM-01852 and P07-FQM-2774), the CNRS and CSIC (Egide Picasso 09543XA and PICS 2008 programmes) are gratefully acknowledged.Peer reviewe

Cooper-Catalyzed Azide-Alkyne Cycloaddition in the Sinthesis of Polydiacetylene: "Click Glycoliposome" as Biosensors for the Specific Detection of Lectins

Supramolecular self-assembly of conjugated diacetylenic amphiphile-tethered ligands photopolymerize to afford polydiacetylene (PDA) functional liposomes. Upon specific interaction with a variety of biological analytes in aqueous solution, PDA exhibits rapid colorimetric transitions. The PDA nanoassemblies, which are excellent membrane mimics, include an ene–yne polymeric reporter responsible for the chromatic transitions and the molecular recognition elements that are responsible for selective and specific binding to the biological target. A bottleneck in the fabrication of these colorimetric biosensors is the preparation of the diacetylenic monomer embedded with the recognition element of choice. In the present work, we make use of copper-catalyzed azide–alkyne cycloaddition (CuAAC) as key step in the preparation of sugar-coated liposome biosensors. The regioselective click ligation of the triacetylenic N-(2-propynyl)pentacosa-10,12-diynamide (NPPCDAM) with a variety of mannose- and lactose-tethered azides afforded chemo- and regioselectively the corresponding 1,2,3-triazole. The obtained diacetylenic monomers were incorporated efficiently into vesicles to afford functional mannose- and lactose-coated glycoliposomes. The obtained PDA-based click glycoliposomes have been characterized by using transmission electronic microscopy (TEM), dynamic light scattering (DLS), and UV/Vis spectroscopy. The efficiency of the reported approach was demonstrated by the rapid optimization of the hydrophilic spacer between the lipidic matrix and the mannose head group for the colorimetric detection of Concavalin A.This work was supported by the DGICyT (grant no. CTQ2010-21755-CO2-01) and the Junta de Andalucía (grant nos. P06-FQM-01852 and P07-FQM-2774). We thank Ms. Rocio Recio for her help with the artwork.Peer Reviewe