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Biomedical subjects

Már Másson

Publications and source records attributed to Már Másson.

16 recordsLinked to original sources
PubMed2006

Development and evaluation of an artificial membrane for determination of drug availability.

Various artificial membranes (e.g. PAMPA) and cellular-based membranes (e.g. Caco-2) are used for screening during early stages of drug discovery. However, these methods are not well suited for evaluation of pharmaceutical formulations and the effects of various excipients on drug availability. When drug molecules permeate biological membranes they encounter two types of permeation resistance, a membrane resistance in the lipophilic membrane and diffusion resistance in the unstirred water layers adjacent to both surfaces of the lipophilic membrane. We have developed an artificial membrane that is cheap and simple to prepare. The unstirred water layer consists of a hydrated semi-permeable cellophane membrane with a molecular weight cutoff (MWCO) of 12,000-14,000 Da and a lipophilic membrane of pure n-octanol in a nitrocellulose matrix. In the diffusion cell the hydrated cellophane membrane (thickness 210-230 microm) is on the donor side and the lipophilic octanol membrane (thickness about 120 microm) on the receptor side. Permeation of ionizable lipophilic drug molecules was diffusion-controlled when the drug was unionized but lipophilic membrane controlled when the drug was ionized. Drug permeation patterns from cyclodextrin containing formulations through the membrane were similar to those previously observed for biological membranes such as hairless mouse skin and the eye cornea.

Animals↗
PubMed2006

Novel water-soluble quaternary piperazine derivatives of chitosan: synthesis and characterization.

Novel synthesis methods for the preparation of quaternary piperazine derivatives of chitosan were developed. Quaternary ammonium moiety can be selectively inserted into either one or both of the piperazine nitrogens, yielding structurally uniform chitosan derivative structures. Water-soluble end products were thoroughly characterized with FT-IR, 1H NMR, 13C NMR and 2D 1H-13C HSQC NMR. The molecular weights of the end products were determined by GPC with triple detection.

Biocompatible Materials↗
PubMed2005

Evaluation of cyclodextrin solubilization of drugs.

The most common stoichiometry of drug/cyclodextrin complexes is 1:1, i.e. one drug molecule forms a complex with one cyclodextrin molecule, and the most common method for stoichiometric determination during formulation studies is the phase-solubility method. However, in recent years it has becoming increasingly clear that solubilizing effects of cyclodextrins are frequently due to the formation of multiple inclusion and non-inclusion complexes. The aqueous solubility of 38 different drugs was determined in pure aqueous solution, aqueous buffer solutions and aqueous cyclodextrin solutions, and the apparent stability constant (K1:1) of the 1:1 drug/cyclodextrin complexes calculated by the phase-solubility method. For poorly soluble drugs (aqueous solubility <0.1mM) the intrinsic solubility (S0) is in general much larger than the intercept of the phase-solubility diagram (Sint) resulting in non-linearity of otherwise linear (AL-type) phase-solubility diagram. This can lead to erroneous K(1:1)-values. A more accurate method for determination of the solubilizing efficiency of cyclodextrins is to determine their complexation efficiency (CE), i.e. the concentration ratio between cyclodextrin in a complex and free cyclodextrin. CE is calculated from the slope of the phase-solubility diagrams, it is independent of both S0 and Sint, and more reliable when the influences of different pharmaceutical excipients on the solubilization are being investigated.

Algorithms↗
PubMed2005

Hydrolysis kinetics and QSAR investigation of soft antimicrobial agents.

Quaternary ammonium surfactants, such as benzalkonium chloride and cetylpyridinium chloride, are commonly used as antibacterial agents for disinfectants and for general environmental sanitation, as well as in surfactants, penetration enhancers and preservatives in pharmaceutical and cosmetic formulations. However, these agents are known to cause various side-effects and toxic reactions that are believed to be associated with their chemical stability. Soft analogues of the long-chain quaternary ammonium compounds were synthesized according to the soft drug approach and their physicochemical properties investigated, such as their hydrolytic rate constant, surface activity and lipophilicity. Structure-activity studies showed that the antimicrobial activity of the compounds was strongly influenced by their lipophilicity and chemical stability, the activity increasing with increasing lipophilicity and stability. However, in soft drug design structure-activity relationships are combined with structure-inactivation relationships during the lead optimization. The safety index (SI) of compounds was defined as the hydrolytic rate constant divided by the minimum inhibitory concentration. The SI of the soft antibacterial agents was found to increase with increasing lipophilicity but optimum SI was obtained when their hydrolytic t1/2, at pH 6 and 60 degrees C, was about 11 h. Optimization of the soft antibacterial agents through SI optimization resulted in potent but chemically unstable quaternary ammonium antibacterial agents.

Benzalkonium Compounds↗
PubMed2005

Investigation of drug-cyclodextrin complexes by a phase-distribution method: some theoretical and practical considerations.

The purpose of the study was to evaluate an octanol-water phase distribution method for investigation of drug/cyclodextrin (D/CD) complexes and to compare stability constant values obtained by this method to values obtained by the phase solubility method. A general equation for determination of 1 : 1 D/CD complex stability constant (K1 : 1) from the slope of a phase-distribution diagram (a diagram of the reciprocal of the apparent partition coefficient vs. the total CD concentration) was derived. The equation accounted for the possible inclusion of the organic solvent in the CD cavity and the gradual saturation of the CD binding with increasing concentration of the guest compound. This method was used to determine K1 : 1 for 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) complexes of hydrocortisone, prednisolone, diazepam, beta-estradiol and diethylstilbestrol. These values were comparable to K1 : 1 values determined by the phase-solubility method. The phase-distribution method could also be applied to determine stability constants for the neutral and ionic forms of the weakly acidic drugs, naproxen and triclosan and the weakly basic drug lidocaine. The phase-distribution method is a very versatile and fast method and has the advantage, compared to the phase-solubility method, that it only requires very small drug samples. Thus, this method would be suitable for screening of new drug candidates.

Chromatography, High Pressure Liquid↗
PubMed2005

Cyclodextrins in drug delivery.

Cyclodextrins are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrin molecules are relatively large with a number of hydrogen donors and acceptors and, thus, in general they do not permeate lipophilic membranes. In the pharmaceutical industry cyclodextrins have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs, and to increase their bioavailability and stability. Studies in both humans and animals have shown that cyclodextrins can be used to improve drug delivery from almost any type of drug formulation. However, the addition of cyclodextrins to existing formulations without further optimisation will seldom result in acceptable outcome. Currently there are approximately 30 different pharmaceutical products worldwide containing drug/cyclodextrin complexes on the market.

Administration, Cutaneous↗
PubMed2004

Self-association of cyclodextrins and cyclodextrin complexes.

Cyclodextrins are useful functional excipients, which are being used in an ever-increasing way to camouflage undesirable pharmaceutical characteristics, especially poor aqueous solubility. It has generally been assumed that the mechanism whereby cyclodextrins exert their effects, especially their augmentation of solubility, is via the formation of noncovalent, dynamic inclusion complexes. This is a model, which regards drug-cyclodextrin interactions as a discrete phenomenon and ignores the possible interaction of these complexes with one another. It is becoming increasingly apparent that such assumptions may not be universally applicable or all encompassing. Specifically, there is a growing body of evidence that supports the important contribution of non-inclusion-based aspects for drug solubilization by cyclodextrins including surfactant-like effects and molecular aggregation. This short review attempts to assess the available literature for areas in which such non-inclusion mechanisms are apparent and tries to interpret these in the context of a broader working theory as to how cyclodextrins exert their beneficial effects.

Cyclodextrins↗
PubMed2003

Soft antimicrobial agents: synthesis and activity of labile environmentally friendly long chain quaternary ammonium compounds.

A series of soft quaternary ammonium antimicrobial agents, which are analogues to currently used quaternary ammonium preservatives such as cetyl pyridinium chloride and benzalkonium chloride, were synthesized. These soft analogues consist of long alkyl chain connected to a polar headgroup via chemically labile spacer group. They are characterized by facile nonenzymatic and enzymatic degradation to form their original nontoxic building blocks. However, their chemical stability has to be adequate in order for them to have antimicrobial effects. Stability studies and antibacterial and antiviral activity measurements revealed relationship between activity, lipophilicity, and stability. Their minimum inhibitory concentration (MIC) was as low as 1 microg/mL, and their viral reduction was in some cases greater than 6.7 log. The structure-activity studies demonstrate that the bioactive compounds (i.e., MIC for Gram-positive bacteria of <10 microg/mL) have an alkyl chain length between 12 and 18 carbon atoms, with a polar headgroup preferably of a small quaternary ammonium group, and their acquired inactivation half-life must be greater than 3 h at 60 degrees C.

Alkylation↗
PubMed2003

The effects of organic salts on the cyclodextrin solubilization of drugs.

Previous studies have indicated that conventional description of drug/cyclodextrin complexes in aqueous solutions as inclusion complexes are not as unambiguous as one might think. It has been shown that in some cases drug/cyclodextrin complexes consist of a mixture of inclusion and non-inclusion complexes. Furthermore it has been shown that drug/cyclodextrin complexes can form aggregates containing up to couple of hundred complexes. In this present study beta-cyclodextrin (betaCD) solubilization of hydrocortisone is enhanced by including short-chain anionic and cationic species in the aqueous complexation medium. For example, maximum hydrocortisone solubility in pure aqueous betaCD solutions or suspensions is 2.2 mg/ml. Addition of 1% (w/v) sodium acetate to the complexation medium increases this value to 7.1 mg/ml (or over 220%). Further addition of 0.25% (w/v) hydroxypropyl methylcellulose to the medium increased the hydrocortisone solubility to over 9 mg/ml. Similar results were obtained when sodium salicylate or benzalkonium chloride were added to the complexation medium. It is also shown that cyclodextrin complexes of lipophilic compounds that have good affinity for the cyclodextrin cavity can be used to enhance cyclodextrin solubilization of drugs that have low affinity for the cavity. All these observations can be explained by formation of drug/cyclodextrin complex aggregates.

Alprazolam↗
PubMed2003

Examination of 19F-NMR as a tool for investigation of drug-cyclodextrin complexes.

Fluorine nuclear magnetic-resonance spectroscopy (19F-NMR) was used to measure complexation of three fluorine-containing drugs--dexamthasone, fluoxetine hydrochloride, and diflunisal sodium--with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). Poor aqueous solubility inhibited investigation of dexamethasone complexes with this method. Complexation caused separation of the fluorine peaks that could be assigned to the two enantiomers of fluoxetine hydrochloride. The trifluoromethyl group of the drug was not included, or only partially included, in the cyclodextrin cavity and the shift changes resulting from complexation were small (0.04 and -0.05 ppm). The NMR method, therefore, could not be used to determine complex stoichiometry and complex stability constants, as chemical-shift changes were influenced by changes in the composition of the solvent medium. The difluorophenyl group of diflunisal sodium was fully included in the cyclodextrin cavity and the chemical-shift changes were large, 2.0 and 1.4 ppm, for C2' and C4' fluorine atoms, respectively. Using the continuous variation method, a 1:1 stoichiometry was determined for the complex. The chemical shift changes could also be used to determine the stability constant (Kc) for complex formation. The value obtained for the fluorine that enters deeper into the cavity was 2000 M(-1). The data shows that, given that the drug has sufficient solubility, one-dimensional 19F-NMR can be a fast and convenient method to investigate drug-cyclodextrin complexes. However, when the results are interpreted it must be taken into account that the solvent medium can affect the chemical shifts of the fluorine peaks.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2002

Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability.

Cyclodextrin complexes of the natural compound curcumin were prepared in order to improve the water solubility and the hydrolytic and photochemical stability of the compound. Complex formation resulted in an increase in water solubility at pH 5 by a factor of at least 10(4). The hydrolytic stability of curcumin under alkaline conditions was strongly improved by complex formation, while the photodecomposition rate was increased compared to a curcumin solution in organic solvents. The cavity size and the charge and bulkiness of the cyclodextrin side-chains influenced the stability constant for complexation and the degradation rate of the curcumin molecule.

Chromatography, High Pressure Liquid↗
PubMed2002

Cyclodextrins and drug permeability through semi-permeable cellophane membranes.

Determinations of drug fluxes through semi-permeable cellophane membranes are used to evaluate cyclodextrin complexes and cyclodextrin containing drug formulations. In the present study we investigated how the cyclodextrin concentration, the membrane thickness and the molecular weight cut off (MWCO) of the membrane influence drug fluxes. The cyclodextrin used was 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and the sample drug was hydrocortisone. The MWCO of the membranes ranged from 500 to 14,000 and the HPbetaCD concentration ranged from 0 to 25% (w/v). The hydrocortisone flux from saturated solutions through the MWCO 500 membrane was unaffected by the cyclodextrin concentration. When MWCO of the membrane was greater than the molecular weight of the complex the flux from solutions saturated with hydrocortisone increased with increasing HPbetaCD concentration. This increase showed negative deviation from linearity. When the flux was corrected for the viscosity increase with increasing HPbetaCD concentration then the flux pattern could be described on the basis of Fick's first law and Stokes-Einstein equation. However, the flux did not correlate with the viscosity when it was increased by adding polymer to the saturated drug solutions. It was shown that the observed flux pattern was consistent with self-association of cyclodextrin complexes in the aqueous donor phase.

Chromatography, High Pressure Liquid↗
PubMed2002

Self-association and cyclodextrin solubilization of drugs.

Phase-solubility diagrams are frequently used to calculate stoichiometry of drug/cyclodextrin complexes. Linear diagrams (A(L)-type systems) are thought to indicate that the complexes are first order with respect to cyclodextrin and first or higher order with respect to the drug. Positive deviation from linearity (A(P)-type systems) are thought to indicate formation of complexes that are first order with respect to the drug but second or higher order with respect to cyclodextrin. The phase solubility of several different compounds, i.e., cholesterol, ibuprofen, diflunisal, alprazolam, 17beta-estradiol and diethylstilbestrol, and various charged and uncharged cyclodextrins was investigated. Phase-solubility diagrams of cholesterol in aqueous cyclodextrin solutions were all of A(P) type. However, the phase-solubility diagrams obtained with charged cyclodextrins could not be fitted to complexes of second or higher order with respect to cyclodextrin. The phase-solubility diagrams of ibuprofen and diflunisal were of A(L) type with slope greater than unity indicating formation of 2:1 drug/cyclodextrin complexes. However, Job's plots and space filling docking studies indicated that 1:1 complexes were formed. These and other observations show that stoichiometry of drug/cyclodextrin complexes cannot be derived from simple phase-solubility studies. Furthermore, the results indicate that drug/cyclodextrin complexes can self-associate to form water-soluble aggregates, which then can further solubilize the drug through non-inclusion complexation.

Cyclodextrins↗
PubMed2002

Cycloserine fatty acid derivatives as prodrugs: synthesis, degradation and in vitro skin permeability.

Various 4,5-dihydroisoxazol-3-yl fatty acid ester derivatives of cycloserine were synthesized to improve skin permeation of cycloserine. The ester derivatives were prepared by using the tert-butoxycarbonyl (t-Boc) protection strategy. The 4,5-dihydroisoxazol-3-yl esters were readily hydrolysed in an aqueous buffer solution, and the degradation profiles showed both specific acid and specific base catalysis. In 50% human serum the formation of cycloserine was observed, but enzymatic catalysis was limited. Delivery through hairless mouse skin was investigated, and the apparent permeability coefficient was measured based on the flux of cycloserine into the receptor phase. The skin permeation of cycloserine across the hairless mouse skin was increased up to 20-fold by the fatty acid esters. The 4,5-dihydroisoxazol-3-yl fatty acid esters of cycloserine can therefore be considered as new topical prodrugs with the potential use in treatment of various skin infections.

Animals↗
PubMedDate not supplied

N-Chloroacyl-6-O-triphenylmethylchitosans: useful intermediates for synthetic modifications of chitosan.

An efficient synthetic route was developed for the mild chloroacylation of chitosan with different chloroacyl chlorides. Full N-chloroacylation was obtained with this procedure without any O-acylation, and products having lower degrees of substitution can also be produced. Organo-soluble 6-O-triphenylmethylchitosan was used as a starting material for the acylation reactions. The resulting N-chloroacyl-6-O-triphenylmethylchitosan intermediates were also organo-soluble and characterized by FT-IR. N-Methylpiperazine moieties were attached to make end products that were sufficiently soluble for characterization by NMR and also to prove that the present intermediates could be used for further modifications. The end products were fully characterized by 1H NMR, 13C NMR, and 2D 1H-13C heteronuclear single-quantum correlation NMR spectroscopy. The degrees of substitution were determined by 1H NMR. Molecular weight determination by GPC-LS displayed a significant degradation of the polymer. The weight-average molar masses (M(w)) of the end products ranged from 29.6 to 49.4 kDa, when the M(w) of the starting material was 144.2 kDa.

Acylation↗