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ABSTRACT: The aim of this work was to develop mucoadhesive hydrogels with variable drug delivery properties by crosslinking poly(acrylic acid) (PAA) with cyclodextrins (CDs). CD-PAA polymers with high CD content and good inter-batch reproducibility were synthesized by activating PAA with SOCl(2), then reacting PAA chloride with CD in the presence of 4-dimethylaminopyridine at 50°C. Manipulation of the synthesis conditions affected the physicochemical character of the CD-PAA polymers and hydrogels in terms of CD content, the average number of ester bonds to an individual CD, viscosity, and the association and release of model drugs. Inclusion complexation of diflunisal (DIF) and fluconazole (FLZ) with CD-PAA hydrogels was assessed by (19)F NMR spectroscopy and association constants (K(a)s) for DIF were in the range 220-486M(-1) with βCD-PAA and 1327-6055M(-1) with hydroxypropyl-βCD-PAA. For FLZ the K(a) range was 34-171M(-1) with hydroxypropyl-βCD-PAA. The hydrogels were found to release both drugs by means of Fickian diffusion as the predominant mechanism. A slight trend towards negative correlation was found between the K(a) and Higuchi k(H) values for DIF. These results highlight the potential of CD-PAA hydrogels to control the release of model drugs through inclusion complexation.
International journal of pharmaceutics 01/2013; · 2.96 Impact Factor
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ABSTRACT: The controlled release of diflunisal and fluconazole from tablets made of novel polymers, poly(acrylic acid) (PAA) crosslinked with either β-cyclodextrin (βCD) or hydroxypropyl-βCD (HPβCD), was investigated and Carbopol 934P (Carbopol) was used as a highly crosslinked PAA for comparison. Diflunisal strongly associates with βCD-PAA and HPβCD-PAA polymers (K (a) of 486 and 6,055 M(-1) respectively); thus, it was physically mixed into the conjugates and also precomplexed to identify whether decomplexation has any influence on release kinetics. Fluconazole has poor complexing ability (K (a) of 34 M(-1) with HPβCD-PAA); thus, it was only tested as a physical mixture. Swelling and adhesion studies were conducted on all tablet combinations and adhesivity of the CD-PAA polymer tablets was maintained. Diflunisal release was much slower from HPβCD-PAA tablets than from βCD-PAA, suggesting that a higher degree of complexation retards release. The precomplexed diflunisal release was also slower than the physically mixed diflunisal of the corresponding conjugate. The release closely followed zero-order kinetics for HPβCD-PAA, but was more sigmoidal for βCD-PAA and especially Carbopol. Conversely, poorly associating fluconazole released in almost exactly the same way across both polymers and Carbopol, indicating that the release kinetics of poorly associating drugs are not influenced by the presence of cyclodextrins. In view of the varying profiles and release rates shown with diflunisal for the different polymers, the fluconazole data support the concept that adequate complexation can indeed modulate the release kinetics of drugs.
AAPS PharmSciTech 01/2013; · 1.43 Impact Factor
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ABSTRACT: The aim of the study was to prepare cationic ISCOMs using cationic derivatives of the saponin Quil A. The polyamines ethylenediamine, spermidine and spermine were conjugated with the glucuronic acid moiety of Quil A. The aqueous solubility of the derivatives increased with decreasing pH, and the pK(a) values were between 6 and 7. The CMCs of the ionised derivatives were around 0.5-1.0 mg/mL. Using the method of hydration of freeze-dried monophase systems, the interaction of each of the Quil A derivatives with phosphatidylcholine and cholesterol, at a mass ratio of 4:4:2 and a pH of 3 and 7.4, was investigated. A few ISCOM-like structures were present in the systems prepared at pH 7.4, hence the ternary system of Quil A spermine derivative, phosphatidylcholine and cholesterol was further investigated at pH 7.4 using a variety of mass ratios. A relatively high number of cationic ISCOM-like structures were observed at the mass ratio of 6:2:2. These ISCOM-like structures were less homogeneous and more irregular in shape than ISCOMs prepared from unmodified Quil A. Colloidal particles with positive zeta potential were produced and may find application in the delivery of nucleic acids or anionic proteins.
International journal of pharmaceutics 05/2009; 376(1-2):123-33. · 2.96 Impact Factor
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ABSTRACT: Nickel-chelating lipids have been synthesized for use as functionalized templates for 2-D crystallization of membrane proteins. These monolayer-forming lipids have been designed with three distinct components: (i) a branched hydrocarbon tail to confer fluidity of the monolayer, (ii) a perfluorinated central core for detergent resistance, and (iii) a nickel-chelating hydrophilic headgroup to facilitate binding of recombinant, polyhistidine-tagged fusion proteins. Alkylations of fluorinated alcohols used in these syntheses proceed in good yields only with the application of prolonged sonication and, in some cases, in the presence of phase-transfer catalysts. Formation of 2-D crystals of the His-tagged membrane protein BmrA from Bacillus subtilis is reported.
The Journal of Organic Chemistry 02/2009; 74(4):1473-9. · 4.45 Impact Factor
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ABSTRACT: Suramin is a polysulfonated polyaromatic symmetrical urea. It is currently used to treat African river blindness and African sleeping sickness. Suramin has also been extensively trialed recently to treat a number of other diseases, including many cancers. Here, we examine its modes of action and discuss its structure-activity relationships.
Mini Reviews in Medicinal Chemistry 12/2008; 8(13):1384-94. · 2.53 Impact Factor
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ABSTRACT: Caco-2 cell permeability and stability assays were used as an in vitro model to study the intestinal epithelial transport and stability of two analogues of thyrotropin-releasing hormone (TRH; Pyr-His-Pro-NH2). Peptide 1 (Pyr-His-Pro-D-glucopyranuronamide) was more permeable across the Caco-2 cell monolayer compared with the permeability of the parent TRH peptide (Papp=5.10+/-1.89x10(-6) cm/s c.f. Papp=0.147+/-0.0474x10(-6) cm/s respectively). The permeability of peptide 1 was improved threefold by attaching a 2-aminooctanoic acid moiety to the N-terminus to form peptide 2 (2-aminooctanoic acid-Gln-His-Pro-D-glucopyranuronamide) (Papp=16.3+/-2.47x10(-6) cm/s). The half-life for both peptide 1 and peptide 2 was approximately 20 min in a homogenate of Caco-2 cells compared with the half-life of TRH which is approximately 3 min. It was concluded that the permeability of peptides 1 and 2 was enhanced because of their increased stability, while the higher permeability of peptide 2 compared with peptide 1 may be attributed to its increased lipophilicity which results in enhanced passive diffusion.
Bioorganic & Medicinal Chemistry 08/2007; 15(14):4946-50. · 2.92 Impact Factor
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ABSTRACT: ISCOMs have received much attention as vaccine adjuvants due to their immunostimulatory effects. They are colloidal particles typically comprised of phospholipids, cholesterol and Quil A, a crude mixture of saponins extracted from the bark of Quillaja saponaria Molina. We have previously shown that ISCOMs can be prepared by ether injection wherein an ether solution of phospholipids and cholesterol in a mass ratio of 5:2 is injected into a solution of Quil A at a mass ratio of 7 lipids: 3 Quil A. The aim of this study was firstly to isolate and characterise discrete fractions of Quil A and secondly to investigate which of these fractions were able to form ISCOMs by the method of ether injection. Six fractions of Quil A were isolated by semi-preparative reverse phase high performance liquid chromatography (RP-HPLC) and characterised by analytical HPLC, liquid chromatography tandem mass spectrometry (LC-MS) and the qualitative Liebermann-Burchard and Molisch tests for triterpenoids and carbohydrates respectively. ISCOMs were subsequently prepared from the isolated fractions by the method of ether injection and the resulting preparations characterized by photon correlation spectroscopy (PCS) and negative stain transmission electron microscopy (TEM). The molecular weights of the major compounds in the fractions ranged from approximately 1200 to approximately 2300 Da; all fractions tested positive for triterpenoids and saccharides and four of the fractions were identified as QS-7, QS-17, QS-18 and QS-21 by analysis (LC-MS and analytical HPLC). Injection of ether solutions of lipids into aqueous solutions of QS-17, QS-18 or QS-21 all resulted in homogeneous ISCOM dispersions. The combination of lipids and QS-7 by ether injection produced lamellae and liposomes as the prominent structures and a minor amount of ISCOMs. The remaining two hydrophilic, low molecular weight fractions of Quil A did not produce ISCOMs, instead liposomes and helical structures predominated in the samples.
Current Drug Delivery 11/2006; 3(4):389-97.
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ABSTRACT: Two polycationic lipophilic-core carbohydrate-based dendrons 2a-b and five polycationic lipophilic-core peptide dendrons 3-6, containing four arginine or lysine terminal residues, were synthesized and then tested in rats as penetration enhancers for the oral delivery of low molecular weight heparin. Better results were obtained with dendrons containing terminal lysine residues than terminal arginine. A significant anti-factor Xa activity was obtained when low molecular weight heparin was coadministered with dendron 5.
Bioorganic & Medicinal Chemistry 02/2006; 14(1):143-52. · 2.92 Impact Factor
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Molbank. 01/2006;
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ABSTRACT: A review with 93 references. Heparins are high molecular weight, hydrophilic polyanions, which are unstable under acidic conditions; and therefore they exhibit poor oral bioavailability. Consequently they must be administered via the parenteral route which is expensive, inconvenient, and limits use by outpatients. The development of an oral form of heparin is warranted. This review examined the literature, mostly published between January 2000 and January 2005, pertaining to the gastrointestinal absorption of heparin by lipidization or coadministration with penetration enhancers. A lipidization strategy that was examined involved conjugation of low molecular weight heparin with deoxycholic acid. The majority of studies examined the ability of different formulations, typically utilizing penetration enhancers, to improve heparin bioavailability. The penetration enhancers used included fatty acids, Labrasol, Gelucire 44/14, polycationic lipophilic-core dendrons, saponins, mono-N-carboxymethyl chitosan, Carbopol 934P, a combination of thiolated polycarbophil and glutathione, polymeric nanoparticles, polymeric microparticles, sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC), and sodium N-[10-(2-hydroxybenzoyl)amino]decanoate (SNAD). The variety of models used and doses of heparin/penetration enhancers applied, however, made it difficult to compare the results between studies. Nevertheless, all of the reviewed drug delivery systems showed therapeutic value and confirmation of the promising results obtained from animal studies, by progression to clinical trials, is necessary. Overall, progress has been made in the quest for an oral heparin formulation.
Current Drug Delivery 08/2005; 2(3):277-87.
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ABSTRACT: The design, synthesis, and evaluation of a liposaccharide (11) for use as an agent to enhance the gastrointestinal absorption of charged, hydrophilic drugs with poor membrane permeability is reported. 11 was designed to possess both surfactant and ion-pairing properties and was conveniently synthesized from d-glucuronic acid (2) and N-Boc-lipoamino acid (5) precursors in eight steps in good yield. Isothermal titration microcalorimetry was used to determine the critical micelle concentration of 11 (in PBS) to be 2.09 +/- 0.01 mM with an enthalpy of demicellization of 4.91 +/- 0.11 kJ/mol. The ability of 11 to enhance the gastrointestinal absorption of the aminoglycoside antibiotic gentamicin (1), a hydrophilic polycation with negligible oral bioavailability, was assessed in vivo using rats. Rats dosed orally with a mixture of 11 (100 mg/kg) and 1 (60 mg/kg) had a statistically significant (P < or = 0.034) increase in Cmax, AUC120, and percent absolute bioavailability (F) compared to control 1 (60 mg/kg) alone. The highest bioavailability (F = 9.1 +/- 2.0%) was achieved by dosing with the mixture 11 (100 mg/kg) and 1 (15 mg/kg). This represents a 6-fold increase in bioavailability compared to the control (F = 1.4 +/- 0.3%). These results suggest that the molar ratio of 1:11 may be critical in optimizing the delivery system, a finding ascribed in part to the ion-pairing properties of 11. The effect of 11 on the gastrointestinal mucosa was assessed using light microscopy to examine tissue samples from rats used in the pharmacokinetic study. No morphological changes were found in either the esophagi or duodena of the rats examined. One rat dosed with 11 (100 mg/kg) and 1 (60 mg/kg) exhibited slight gastric erosion, which could be attributed to 11.
Journal of Medicinal Chemistry 02/2004; 47(5):1251-8. · 5.25 Impact Factor
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ABSTRACT: To synthesize a number of analogues of Leu-enkephalin with different lipophilicities and to develop an LC-MS method for determining the Caco-2 cell permeability values of these compounds.
A number of sugar and sugar plus lipoamino acid analogues of Leu-enkephalin were synthesized by solid-phase and solution methods. An LC-MS method was developed for analyzing the Caco-2 cell assay samples and validated against the traditional method using radiolabelled compounds.
A sensitive and specific LC-MS assay was developed. Standard curves were linear in the range of 0.025-5 microM. Apparent permeability values determined by LC-MS and liquid scintillation counter were identical, for both a hydrophilic drug, cephalexin and a lipophilic Leu-enkaphalin analogue. Caco-2 permeability values for the analogues of Leu-enkephalin were determined and it was found that attachment of sugar or sugar and lipoamino acid to the Leu-enkephalin peptide resulted in an increase in the apparent permeability values compared to the native peptide, which was not transported across the Caco-2 cell monolayers.
A rapid, generic LC-MS method for analyzing a range of compounds was developed. Attachment of a sugar or sugar and lipoamino acid to Leu-enkephalin improves the apparent permeability across Caco-2 cell monolayers.
European Journal of Pharmaceutical Sciences 09/2002; 16(3):113-8. · 3.21 Impact Factor
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ABSTRACT: The co-administration of a drug with a penetration enhancer (PE) is one method by which the membrane permeability of a drug can be improved. To facilitate PE design, it is important that the molecular basis of PE toxicity and efficacy be examined, so we investigated the membrane affinity and micellar aggregation of a series of synthetic liposaccharide PEs and correlated these properties with hemolytic potency. The influence of liposaccharide alkyl chain length (nc) on the system was studied, and comparisons were made with conventional PEs such as bile salts, fatty acids, and surfactants. The liposaccharides were each synthesized in eight steps in good overall yield. Their critical micelle concentrations (CMCs) in phosphate-buffered saline ranged from 0.207 to 20.2 mM, and it was found that increasing nc by 2 afforded a 1 order of magnitude decrease in the CMC. Immobilized artificial membrane (IAM) chromatography was used to determine each PE's affinity for biological membranes, and an increase in nc caused a significant increase in the extent of membrane binding. A study of hemolytic activity revealed that liposaccharides with an nc of < or = 12 are the most likely to be biocompatible. The CMC values for all PEs showed a negative correlation with hemolytic potency; however, it was PE monomers, not micelles, that were responsible for the onset of hemolysis. The affinity of all enhancers for the IAM displayed a positive correlation with hemolytic potency, and therefore, IAM chromatography can be used to predict PE hemolytic activity. It was concluded that the biocompatibility of liposaccharides can be modulated by minor alterations in nc.
Molecular Pharmaceutics 1(3):233-45. · 4.78 Impact Factor
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ABSTRACT: The use of lipid monolayers to bind and adsorb proteins is an attractive and increasingly important method for generating high localized concentrations of oriented proteins and protein complexes. These bound proteins can be imaged directly, or they may form 2-D crystalline arrays that are amenable to structure determination by single particle analysis or 2-D electron crystallography. 2-D crystals grown by this technique can also be used to initiate the growth of 3-D crystals for X-ray diffraction analysis. Many derivatized lipids have been prepared for use with this technique, incorporating a diverse range of ligands to enable binding to specific proteins. Synthetic lipids containing functionalized head groups that chelate Ni2+ or Cu2+ have also been prepared to bind and orient expressed proteins that contain His-tags. Protein-binding monolayer-forming lipids generally consist of two distinct components: (1) a branched hydrocarbon tail to confer fluidity to the monolayer and (2) a functionalized hydrophilic head group to facilitate binding of protein molecules at the air-water interface. Newer examples of these compounds also incorporate perfluorinated hydrocarbon moieties to confer detergent resistance to these lipids. This review focuses on synthetic approaches to functionalized lipids for protein monolayer crystallizations.
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ABSTRACT: Epoxides have been transformed in good yields to alkenes by a process involving (i) ring-opening of the epoxide with 2-mercaptobenzothiazole, (ii) oxidation of the derived -hydroxy thioethers to the corresponding sulfones, and (iii) thermal or base-promoted fragmentation of these sulfones to alkenes. The stereochemistry of the starting epoxide is transfer-red faithfully to the alkene product, because of the SN2 epoxide ring-opening reactions and the antiperiplanar SO2 elimination reaction of the - alkoxysulfinate intermediates. This methodology may form the basis of a new protecting group strategy for alkenes. 2010 Wiley-VCH Verlag GmbH & Co. KGaA.
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ABSTRACT: An approach to the synthesis of suramin analogues has been realised, which avoids synthetic problems associated with conventional routes. The use of isobutyl ester protecting groups for sulfonic acids was crucial to the success of the strategy, because these were able to be cleanly deprotected with sodium iodide, yielding the sodium salts of the corresponding sulfonic acids. (C) 2009 Elsevier Ltd. All rights reserved.
