Hanne Hjorth Tønnesen

Alginate in Drug Delivery Systems

ABSTRACT Alginates are established among the most versatile biopolymers, used in a wide range of applications. The conventional use of alginate as an excipient in drug products generally depends on the thickening, gel-forming, and stabilizing properties. A need for prolonged and better control of drug administration has increased the demand for tailor-made polymers. Hydrocolloids like alginate can play a significant role in the design of a controlled-release product. At low pH hydration of alginic acid leads to the formation of a high-viscosity “acid gel.” Alginate is also easily gelled in the presence of a divalent cation as the calcium ion. Dried sodium alginate beads reswell, creating a diffusion barrier decreasing the migration of small molecules (e.g., drugs). The ability of alginate to form two types of gel dependent on pH, i.e., an acid gel and an ionotropic gel, gives the polymer unique properties compared to neutral macromolecules. The molecule can be tailor-made for a number of applications. So far more than 200 different alginate grades and a number of alginate salts are manufactured. The potential use of the various qualities as pharmaceutical excipients has not been evaluated fully, but alginate is likely to make an important contribution in the development of polymeric delivery systems. This natural polymer is adopted by Ph.Eur. It can be obtained in an ultrapure form suitable for implants. This review discusses the present use and future possibilities of alginate as a tool in drug formulation.

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.

Studies on curcumin and curcuminoids

ZusammenfassungEs wurde die Kinetik des pH-abhängigen Curcumin-Abbaus untersucht. Eine Darstellung der Geschwindigkeitskonstante gegen die pH-Werte liefert die pKa-Werte des sauren Protonen. Diese Kurve zeigt aber gleichzeitig die Komplexität des Curcumin-Abbaus an.SummaryThe kinetics of the pH-dependant degradation of curcumin has been investigated. A plot of the rate constant against pH indicates the pKa values of the acid protons. The graph also indicates the complexity of the curcumin degradation.

Corrected Emission Spectra and Quantum Yields for a Series of Fluorescent Compounds in the Visible Spectral Region

The increased use of steady-state and dynamic fluorescence measurements to address chemical problems is directly attributable to its sensitivity and selectivity as well as innovations and developments in measurement systems. Additionally, during the last two decades fluorescence applications to biochemical measurement problems have increased tremendously, especially through the development of new fluorescent ligands and their inclusion in antibody techniques. In these developments and applications, however, accurate measurements and comparability of results among various laboratories are critical for continued progress and are dependent on the availability of fluorescence standards for both steady-state and dynamic measurements. It is important that laboratories, especially National Standards Laboratories, develop fluorescence standards that research laboratories can use so that the research laboratories can focus their efforts on measurements, applications and chemical breakthroughs, rather than developing standards to ensure that their measurements are accurate and transferable. The issuance [1] of the first fluorescence Standard Reference Material, Quinine Sulfate Dihydrate (SRM 936) in the late 1970’s [2] was a step in this direction and has been followed by reports at workshops that included the continuing need for and research on additional fluorescence standards [3]. Magde et al. [4] have recently provided absolute quantum yields by a thermal blooming technique for rhodamine 6g and fluorescein in various solvents. They also used these data with earlier reported lifetimes [5] to cal-

Studies on curcumin and curcuminoids VIII. Photochemical stability of curcumin

ZusammenfassungDie photochemische Stabilität von Curcumin wurde untersucht und die Hauptprodukte der Spaltung identifiziert. Die Abbau- und Halbzeit-Reaktionen des Curcumins in verschiedenen Lösungsmitteln und im festen Zustand werden beschrieben.SummaryThe photodecomposition of curcumin when exposed to UV/visible radiation is studied. The main degradation products are identified. The reaction mechanisms are investigated and the order of the over-all degradation reactions and the half-lives of curcumin in different solvents and in the solid state are determined.

Formulation and stability testing of photolabile drugs

Exposure of a drug to irradiation can influence the stability of the formulation, leading to changes in the physicochemical properties of the product. The influence of excipients of frequently used stabilizers is often difficult to predict and, therefore, stability testing of the final preparation is important. The selection of a protective packaging must be based on knowledge about the wavelength causing the instability. Details on drug photoreactivity will also be helpful in order to minimize side-effects and/or optimize drug targeting by developing photoresponsive drug delivery systems. This review focuses on practical problems related to formulation and stability testing of photolabile drugs.

Studies on curcumin and curcuminoids. XXIX. Photoinduced cytotoxicity of curcumin in selected aqueous preparations

Natural curcumin was evaluated as a potential photosensitizer for oral applications. The photocytotoxicity of curcumin on salivary gland acinar cells (SM 10-12) was investigated in five aqueous preparations consisting of 5% DMSO, non-ionic micelles, cyclodextrin, liposomes, or a hydrophilic polymer. The difference in phototoxic effects between natural curcumin and synthetic curcumin was examined. Cytotoxicity in SM 10-12 cells exposed to curcumin in the concentration range 0.4-13.5 microM was investigated by MTT test, a fluorescence-staining microscopic test, and by Western immunoblotting techniques. The potential formation of a photoreaction product, hydrogen peroxide, was evaluated by a fluorescence assay. The light source was a halogen lamp used in the dental clinic, emitting mainly in the blue part of the spectrum. The phototoxic effect on SM 10-12 cells was dependent on curcumin concentration, the light dose and the type of preparation. Natural and synthetic curcumin induced phototoxicity to the same extent. Significant effects on the cells were obtained at low curcumin concentrations (< or =0.5 microM) and at a low light dose (< or =6 J cm(-2)), after 3 h incubation. Neither the activation of caspases-3, -7, -8 or -9, nor the formation of hydrogen peroxide could be detected in cells exposed to curcumin and light. The liposome preparation was the most efficient vehicle for curcumin to induce cell death. The phototoxic effect induced by curcumin is highly dependent on the type of preparation. Curcumin might be a potential photosensitizer in the treatment of oral lesions and cancers provided careful selection of the vehicle.

Role of H-bond formation in the photoreactivity of curcumin ∗

Curcumin is the main constituent of curry. In its ground state it shows chemo-preventive, chemo-therapeutic and anti-inflammatory effects. For its immunostimulating action it has been considered for the development of drugs suitable for treating AIDS and cystic fibrosis. Further biological action is induced in curcumin by photoactivation: in suitable environmen- tal conditions electronically excited curcumin can act as a singlet oxygen generator. Moreover, cytotoxicity is enhanced by light exposure and antibacterial effects are photosensitized. This work is aimed to understand the photobiological action of curcumin by elucidating the deactivation mechanisms of its first excited singlet state. In particular we find evidence of the role of tautomerization in the excited state by measuring fluorescence lifetimes and quantum yields for such compound dissolved in solvents of different polarity and H-bonding capability. Degradation quantum yield and singlet oxygen generation efficiency were also measured in acetonitrile and methanol. The results emphasize the strong dependence of the deactivation processes from the environment. The deactivation phenomenology can be fully explained by postulating intramolecular proton transfer in the cis enol conformer to be the leading non-radiative deactivation pathway.

Formulation and bacterial phototoxicity of curcumin loaded alginate foams for wound treatment applications: Studies on curcumin and curcuminoides XLII

Curcumin loaded alginate foams are proposed for application in antimicrobial photodynamic therapy of infected wounds. The drug loaded foams were formulated to provide a burst release of the photosensitizer when hydrated. The foams remained intact after hydration and would be possible to remove from the wound prior to irradiation without causing any tissue damage. The characterization of the prepared foams showed that both curcumin loaded and unloaded foams hydrated within 1  min and absorbed from 12 to 16 times their dry weight of a model physiological fluid. Curcumin, the model photosensitizer, has an extremely low solubility in water and may aggregate in aqueous environment. Cyclodextrins (CDs) and polyethylene glycol 400 (PEG 400) were therefore selected as solubilizers of curcumin in the foams to provide a burst release of the photosensitizer. Exposure to the prepared foams in combination with visible light irradiation (∼9.7  J/cm(2)) resulted in >6  log reduction of Entrococcus faecalis cells. However, curcumin mediated photokilling of Escherichia coli was ineffective when CDs were selected as solubilizer of curcumin in the foams. An 81% reduction in viable E. coli cells was detected after treatment with the foam containing PEG 400 as the only solubilizer of curcumin combined with visible light irradiation (∼29  J/cm(2)).

PHOTOPHYSICAL STUDIES ON ANTIMALARIAL DRUGS

Abstract— Most drugs used in the treatment of malaria produce phototoxic side effects in both the skin and the eye. Cutaneous and ocular effects that may be caused by light include changes in skin pigmentation, corneal opacity, cataract formation and other visual disturbances including irreversible retinal damage (retinopathy) leading to blindness. The mechanism for these reactions in humans is unknown. We irradiated a number of antimalarial drugs (amodiaquine, chloroquine, hydroxychloroquine, mefloquine, primaquine and quinacrine) with light (Λ > 300 nm) and conducted electron paramagnetic resonance (EPR) and laser flash photolysis studies to determine the possible active intermediates produced. Each antimalarial drug produced at least one EPR adduct with the spin‐trap 5,5‐dimethyl‐l‐pyrroline N‐oxide in benzene: superoxide/hydroperoxyl adducts (chloroquine, mefloquine, quinacrine, amodiaquine and quinine), carbon‐centered radical adducts (all but primaquine), or a nitrogen‐centered radical adduct only (primaquine). In ethanol all drugs except primaquine produced some superoxide/hydroperoxyl adduct, with quinine, quinacrine, and hydroxychloroquine also producing the ethoxyl adduct. As detected with flash photolysis and steady‐state techniques, mefloquine, quinine, amodiquine and a photoproduct of quinacrine produced singlet oxygen (τ= 0.38; τ= 0.36; τ= 0.011; τ= 0.013 in D2O, pD7), but only primaquine quenched singlet oxygen efficiently (2.6 × 108M−1 s1 in D2O, pD7). Because malaria is a disease most prevalent in regions of high light intensity, protective measures (clothing, sunblock, sunglasses or eye wraps) should be recommended when administering antimalarial drugs.