Cetuximab Conjugated with Octreotide and Entrapped Calcium Alginate-beads for Targeting Somatostatin Receptors.

There is a need to formulate oral cetuximab (CTX) for targeting colorectal cancer, which is reported to express somatostatin receptors (SSTRs). Therefore, coating CTX with a somatostatin analogue such as octreotide (OCT) is beneficial. Alginate was used to coat CTX to facilitate delivery to the gastrointestinal tract (GIT). This study aimed to deliver CTX conjugated with OCT in the form of microparticles as a GIT-targeted SSTR therapy. Both CTX and OCT were conjugated using a solvent evaporation method and the conjugated CTX-OCT was then loaded onto Ca-alginate-beads (CTX-OCT-Alg), which were characterized for drug interactions using differential scanning calorimetry (DSC), and Fourier transform infrared spectra (FTIR). Moreover, the morphology of formulated beads was examined using a scanning electron microscope (SEM). The drug content and release profile were studied using UV spectroscopy. Finally, in vitro cytotoxicity of all compounds was evaluated. The results showed homogenous conjugated CTX-OCT with a diameter of 0.4 mm. DSC showed a delay in the OCT peak that appeared after 200 °C due to small polymer interaction that shifted the OCT peak. Moreover, FTIR showed no prominent interaction. SEM showed clear empty cavities in the plain Ca-alginate-beads, while CTX-OCT-Alg showed occupied beads without cavities. CTX-OCT-Alg had a negligible release in 0.1 N HCl, while the CTX-OCT was completely released after 300 min in phosphate buffer pH 7.4. All formulations showed good antiproliferative activity compared with free drugs. The formulated CTX-OCT-Alg are a promising platform for targeting colorectal cancer through GIT

Razvoj i fizikokemijsko vrednovanje farmakosoma diklofenaka

Pharmacosomes are amphiphilic lipid vesicular systems that have shown their potential in improving the bioavailability of poorly water soluble as well as poorly lipophilic drugs. Diclofenac is a poorly water soluble drug and also causes gastrointestinal toxicity. To improve the water solublity of diclofenac, its pharmacosomes (phospholipid complex) have been prepared and evaluated for physicochemical analysis. Diclofenac was complexed with phosphatidylcholine (80 %) in equimolar ratio, in the presence of dichloromethane, by the conventional solvent evaporation technique. Pharmacosomes thus prepared were evaluated for drug solubility, drug content, surface morphology (by scanning electron microscopy), phase transition behaviour (by differential scanning calorimetry), crystallinity (by X-ray powder diffraction) and in vitro dissolution. Pharmacosomes of diclofenac were found to be irregular or disc shaped with rough surfaces in SEM. Drug content was found to be 96.2 1.1 %. DSC thermograms and XRPD data confirmed the formation of the phospholipid complex. Water solubility of the prepared complex was found to be 22.1 µg mL1 as compared to 10.5 µg mL1 of diclofenac. This improvement in water solubility in prepared pharmacosomes may result in improved dissolution and lower gastrointestinal toxicity. Pharmacosomes showed 87.8 % while the free diclofenac acid showed a total of only 60.4 % drug release at the end of 10 h of the dissolution study.Farmakosomi su amfifilni lipidni vezikularni sustavi sa sposobnošću poboljšanja bioraspoloživosti lijekova slabo topljivih u vodi i organskim otapalima. U svrhu povećanja topljivosti diklofenaka (ljekovite tvari koja je slabo vodotopljiva, a uzrokuje i gastrointestinalnu toksičnost) pripravljeni su i evaluirani njegovi farmakosomi (fosfolipidni kompleksi). Diklofenak je kompleksiran s fosfatidilkolinom (80 %) u ekvimolarnom omjeru, u prisutnosti diklormetana, konvencionalnom metodom evaporacije. Tako pripravljenim farmakosomima ispitivana je topljivost, sadržaj ljekovite tvari, morfologija površine (pomoću pretražne elektronske mikroskopije), ponašanje pri prijelazu faza (pomoću diferencijalne pretražne kalorimetrije), kristaliničnost (rendgenskom analizom praha) i in vitro oslobađanje. Farmakosomi diklofenaka su nepravilnog oblika ili u obliku diska te imaju neravnu površinu u SEM-u. Sadržaj ljekovite tvari je 96,2 1,1 %. DSC termogrami i XRPD podaci potvrdili su nastajanje fosfolipidnog kompleksa. Topljivost u vodi dobivenih kompleksa bila je 22,1 µg mL1, a topljivost samog diklofenaka 10,5 µg mL1. Postignuto poboljšanje topljivosti može imati za posljedicu povećano oslobađanje i manju gastrointestinalnu toksičnost. Tijekom 10 h iz farmakosoma se oslobodilo 87,8 %, a iz slobodnog diklofenaka samo 60,4 % ljekovite tvari

Study of dissolution kinetics for poorly water-soluble drugs from ternary interactive mixtures in comparison with commercially available capsules

Objective: The main objective of this work was to study the dissolution kinetics of poorly water-soluble drugs, indomethacin and ibuprofen, from formulated capsules or interactive mixtures containing fine lactose (FL), as ternary additive, and coarse lactose as carrier compared with selected commercially indomethacin capsules and to investigate the role of FL-drug size ratio on the dissolution. Results and Discussion: It was found that the addition of FL in lactose-indomethacin capsules enhanced the dissolution of indomethacin while it has decreased the dissolution of ibuprofen from the lactose-ibuprofen mixtures. The particle size distributions for drugs and fine lactose used in this study suggested that the difference in dissolution behaviour for the two drugs could be due to the FL-drug ratio. Results obtained from the application of different dissolution kinetic equations showed that the first-order equation can best describe the kinetic of the dissolution for Rothacin®, Indylon®, Indomin® and ternary-formulated capsules of indomethacin, while the dissolution from the binary-formulated indomethacin capsules showed that the dissolution cannot be described by zero-order or first-order equations. For ibuprofen mixtures, the results showed that the release followed the first-order kinetic for both systems, binary and ternary mixtures. Results obtained from Peppas equation showed that all indomethacin formulations used in this study released the drug by Fickian release with release exponent (n) < 0.45, while all ibuprofen formulations used in this study released the drug by non-Fickian (anomalous) release with release exponent (n) > 0.45 and > 0.89. Conclusion: The FL-drug ratio could give an explanation to the enhanced dissolution of indomethacin and decreased dissolution of ibuprofen from interactive mixtures

Superhydrophobic condenser surfaces for air gap membrane distillation

Superhydrophobic surfaces for enhanced condensation in air gap membrane distillation (AGMD) may provide significantly improved distillate production rates and increased thermal efficiency. While AGMD is one of the most thermally efficient membrane distillation desalination configurations, large transport resistances in the air gap limit distillate production rates. AGMD experiments were performed with combinations of untreated, hydrophobic, and superhydrophobic condensation surfaces. A nanostructured copper oxide coated condensing surface produced durable 164°±4° contact angles and jumping droplet condensation. Tests were also performed on the air gap spacer, in this case a small diameter support mesh, to judge the effects of superhydrophobic treatment and conductivity on distillate production for AGMD. A novel visualization technique was implemented to see through PVDF membranes and confirm air gap behavior. The experiments were compared with numerical modeling of AGMD film-wise condensation and flooded-gap MD. The results indicate that the introduction of superhydrophobic surfaces can result in improvements in distillate production in excess of 60% over standard AGMD. However, for high distillate production, condensation on the superhydrophobic plate transitions from a partially wetted droplet morphology to Wenzel flooded (wetting) conditions. Mildly hydrophobic condensing surfaces were found to provide moderate improvement in distillate production. Superhydrophobic support meshes made a negligible difference in distillate production, but high conductivity support meshes showed significant increases in flux at the expense of increased conduction losses. The results outline recommended superhydrophobic condensation conditions at varied feed and cold side temperatures for substantial improvement to distillate production rate for AGMD systems in a flat plate configuration.Masdar Institute of Science and Technology (Massachusetts Institute of Technology Cooperative Agreement 02/MI/MI/CP/11/07633/GEN/G/00

In-vitro cytotoxic/cytostatic activity of anionic liposomes containing vinblastine against leukaemic human cell lines

Liposomes prepared from lipids dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) with cholesterol were used to investigate the percentage of vinblastine encapsulation and the influence of lipid composition on the retention properties of vinblastine in buffer as well as in cell culture medium. Differential scanning calorimetry (DSC) was applied, to study the effect of cholesterol on the phase transition temperature and on the ΔH of the two liposome formulations. The cytotoxic and cytostatic activity of the liposome-encapsulated vinblastine was also examined against six leukaemic human cell lines. The results showed that encapsulation of vinblastine into liposomes was greater than 98% with a drug-phospholipid molar ratio of 0.13-0.18. The major improvement in vinblastine retention in buffer as well as in culture medium was achieved by employing DPPG. The DSC data showed that vinblastine exerted a more perturbing effect in DPPC-cholesterol bilayers than in DPPG-cholesterol bilayers and this may explain their lower retention time. The 50% growth-inhibiting (GI50) and cytostatic (TGI) activity of liposomal vinblastine did not seem to be affected by the type of the liposome while the 50% cytotoxic activity (LC50) was affected in four out of the six cell lines tested. The parameters GI50, TGI and LC50 were estimated according to the instructions given by the NCI

The modulation of thermal properties of vinblastine by cholesterol in membrane bilayers

lt has been shown that the partitioning of vinblastine in 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) single and multiple bilayer dispersions induces partial interdigitation of the lipid alkyl chains. Similar behavior has been observed for abietic and ursodeoxycholic acids and may well be generalized for the partitioning of bulky amphoteric molecules, which tend to localize in the vicinity of the polar heads. For the present study, differential scanning calorimetry (DSC) has been employed to investigate the role of lipid molecular characteristics such as the alkyl chain length and the polarity of the head-group, as well as the impact of cholesterol upon vinblastine-induced interdigitation. It is found that vinblastine does not induce interdigitation in lipids with either shorter or longer alkyl chains than DPPC, or having head-groups of different polarity. In addition, it is shown that the presence of cholesterol in the lipid bilayer tends to modulate the phase behavior of the lipid/vinblastine bilayer system. Preliminary studies show that such properties directly affect the encapsulation efficiency and the pharmacokinetics of liposomes. (C) 2003 Elsevier B.V. All rights reserved