Aggregation Of Cyclodextrins Research Articles

Effect of self-aggregation of γ-cyclodextrin on drug solubilization

The purpose of this study was to investigate the physicochemical properties of drug-saturated aqueous cyclodextrin (CD) solutions. Phase solubility profiles of different drugs were determined in aqueous solutions containing γ-cyclodextrin (γCD) and/or hydroxypropyl-γ-cyclodextrin (HPγCD) in absence or presence of water-soluble polymers. 1H-NMR and turbidity analysis were performed as well as permeation studies. Phase solubility diagrams showed that the observed γCD content (1–20% w/v) was only slightly different from the theoretical values for aqueous solutions that had been saturated with indomethacin, diclofenac sodium or amphotericin B, all displayed A-type profiles, while it was less than the theoretical value in solutions that had been saturated with corticosteroids (hydrocortisone and dexamethasone) that displayed BS-type profiles. In the latter case self-assemble of drug/CD complexes decreased the overall CD solubility. Water-soluble polymers enhanced aqueous solubility of the drugs tested by stabilizing the drug/CD complexes, i.e. enhancing their stability constants, without affecting the observed aqueous γCD solubility. When the drug solubility leveled off (the BS-type profiles) the amount of dissolved γCD increased and approached the theoretical values. Hydrocortisone formed partial inclusion complex with γCD and HPγCD and no non-inclusion or aggregates could be detected in diluted solutions by 1H-NMR. Both permeation and turbidity studies showed that formation of dexamethasone/γCD complex promoted CD aggregation. All these observations indicate that CD aggregate formations play a role in CD solubilization of lipophilic and poorly water-soluble drugs and that the water-soluble polymers enhance the complexation efficiency of γCD and HPγCD by stabilizing the self-assembled drug/CD nanoparticles and promote non-inclusion complex formation.

Drug/cyclodextrin: beyond inclusion complexation

Development of cyclodextrins as enabling excipients began decades ago and during this time a conventional view of the substrate–cyclodextrin interaction was formed that has persisted in spite of numerous contradicting observations. Here the shortcomings of the phase-solubility method are elucidated. The limited permeability of drug/cyclodextrin complexes through semi-permeable membrane, as well as osmometric data and images from transition electronic microscopy (TEM) are used as convincing evidences of aggregation of cyclodextrins and their complexes. The necessity of updating the existing notions of cyclodextrin complexation is discussed.

Cyclodextrins as solubilizers: Formation of complex aggregates

Three different techniques were applied to investigate aggregation of drug/cyclodextrin complexes, that is, drug permeation through semi-permeable membranes, determination of changes in the value of activity coefficients of drug/cyclodextrin complex solutions and transmission electron microscopy (TEM). The aqueous solutions studied contained γ-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin or mixtures thereof, and hydrocortisone, amphotericin B, diclofenac sodium or indomethacin. The permeation studies indicated that drug/cyclodextrin complex monomers (i.e., unaggregated complexes) were dominating at cyclodextrin concentrations below 5% (w/v). Then formation of aggregates gradually increased with increasing cyclodextrin concentration until all increase in dissolved drug/cyclodextrin complexes was due to formation of cyclodextrin aggregates. This happened even though the observed phase-solubility diagrams were linear, that is, were of AL-type. The activity coefficients showed positive deviation from ideal state. This positive deviation is due to concurrent of several processes, that is, hydration, aggregation and complex formation. The observed deviations from ideality indicated that complex aggregates were formed in the aqueous complexation media. TEM pictures showed formation of aggregates in both pure aqueous cyclodextrin solutions as well as in cyclodextrin solutions that had been saturated with hydrocortisone. The aggregate diameter was between 10 and 100 nm but larger aggregates with diameter of about 200 nm were formed through assemble of smaller aggregates. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:719–729, 2010

Supramolecular Colloidal Systems of Gold Nanoparticles/Amphiphilic Cyclodextrin: a FE-SEM and XPS Investigation of Nanostructures Assembled onto Solid Surface

Properly functionalized amphiphilic cyclodextrins (CDs) can act as capping agents for gold colloids in solution (Mazzaglia, A.; et al. J. Phys. Chem. C 2008, 112, 6764). In the present work, we report a study on a hybrid gold nanoparticles/amphiphilic CD supramolecular system assembled onto a surface by both field emission scanning electron microscopy (FE-SEM) and X-ray photoelectron spectroscopy (XPS) techniques. Amphiphilic CDs bearing respectively thioalkyl chains with different length in the primary site (thiohexyl in SC6NH2 and thiohexadecyl in SC16NH2) and oligoethylene amino groups in the secondary ones were drop-cast onto glass and silicon surfaces. FE-SEM pointed out on the mesoscopic scale the presence of CDs aggregates with sizes of about 100−300 nm, mostly displaying the known vesicular aspect. Both CDs can interact closely with gold nanoparticles of 10−20 nm. The binding mode was investigated in detail by XPS pointing to the coordination of CD amino groups with the external thin shell of gold...

Drug Targeting to the Hair Follicles: A Cyclodextrin-Based Drug Delivery

Topical drug delivery systems that selectively target hair follicles and sweat glands are of interest to both the pharmaceutical and the cosmetic industry not only to treat dermal complications but also for systemic drug delivery (1,2). Possible dermal applications include treatment of acne, inflammation, and hair growth disorders. Hair follicles are tube-like pockets of the epidermis that extend through most or all of the depth of the skin and enclose a small papilla of dermis in their base. The hair bulb, which lies at the base of the hair follicle, is a structure of actively growing cells that eventually produce the long fine cylinder of a hair. Attached to the follicle are one or more sebaceous glands. The hair shaft is enveloped in an inner root sheath that consists of keratin-rich cells that have migrated from the growing cells that line the inside of the hair follicles (Fig. 1). Microparticulate vehicles, like liposomes (2,3) and nanoparticles (4), have been shown to deliver drug molecules much deeper into the hair follicles than conventional formulations like creams and ointments. It has been shown that liposomes and nanoparticles with diameter between 300 and 750 nm penetrate preferentially into the hair follicles (5) and that titanium dioxide particles with a diameter of about 100 nm penetrate into the hair follicles (6). Fig. 1 A schematic drawing of a hair follicle Cyclodextrins (CDs) are cyclic oligosaccharides that have in recent years been introduced to the pharmaceutical industry as novel enabling excipients, mainly as solubilizing complexing agents for enhanced drug bioavailability (7,8). CDs consist of six (αCD), seven (βCD), eight (γCD), or more α-1,4-linked α-d-glucopyranose units forming a somewhat truncated cone. The hydroxy groups are oriented towards the cone exterior, making the external surface hydrophilic, while the central cavity is lined by the carbons and ethereal oxygens of the carbohydrate skeleton, making it somewhat hydrophobic. CDs form inclusion complexes by taking up a lipophilic drug molecule, or more frequently some lipophilic moiety on the drug molecule, into the lipophilic central cavity. Although such inclusion complexes are probably the most common form of drug/CD complexes, the hydroxy groups on the outer surface of the CD molecule are able to form hydrogen bonds with other molecules, and CDs can, like non-cyclic oligosaccharides and polysaccharides, form water-soluble non-inclusion complexes with lipophilic water-insoluble drugs (9–11). In saturated aqueous solutions, drug/CD complexes frequently consist of a mixture of inclusion and non-inclusion complexes. CDs and CD complexes are also known to self-associate to form nanoscale aggregates (12–14), and these aggregates are thought to be able to solubilize lipophilic drug molecules in micellar-like fashion (15). The diameter of these cyclodextrin aggregates has been determined to be about 100 to 600 nm (13,14,16). Thus, it is possible that drug/CD complexes will, like liposomes and nanoparticles, selectively target the hair follicles. The purpose of this study was to evaluate follicular targeting potential of drug/CD complexes using curcumin as a sample compound. Curcumin, a lipophilic fluorescent dye, is a non-toxic natural compound with very limited solubility in water. Curcumin forms water-soluble cyclodextrin complexes (17). Previously, curcumin has been used to detect follicular penetration from liposome formulations by laser scanning microscopy using pig skin as a model tissue (3,18,19).

Self-Assembly of β-Cyclodextrin in Water. 2. Electron Spin Resonance

The interaction of amphipilic spin labels with beta-cyclodextrin was investigated using conventional electron spin resonance (ESR) spectroscopy to explore the aggregation of cyclodextrins in water. Methyl 5-doxylstearate (5-DMS) and stearic acid spin probes (n-DSA), which contain a cyclic nitroxide moiety with unpaired electrons covalently linked to the aliphatic chain carbon in positions 5, 7, 12, and 16, show that different dynamic domains coexist in beta-CD water solutions above 3 mM. The results are consistent with the formation of beta-CD self-assembled structures in water above a critical aggregation concentration and confirm the previous findings that were reported in the part 1 article of this series.

Aggregation of Cyclodextrins as an Important Factor to Determine Their Complexation Behavior

Here, we report a study on the complexation behavior of carotenoids with cyclodextrins (CDs) using solubility experiments and molecular-modelling methods. Carotenoids are an important group of naturally occurring dyes found in vegetables and fruits. Their antioxidant property has initiated investigations on their possible use as drugs. However, carotenoids are lipophilic molecules with very little inherent aqueous solubility. Cyclodextrin complexation has been widely used in order to increase the potential applications of hydrophobic compounds. Thus, the aim of our investigation was to design carotenoids with enhanced water solubility by cyclodextrin complexation. Molecular modelling of carotenoid-cyclodextrin complexes with a 1 : 1 stoichiometry successfully explained the experimentally observed capability of beta-cyclodextrins (beta-CDs) to form complexes with carotenoids as opposed to alpha-cyclodextrins (alpha-CDs) and gamma-cyclodextrins (gamma-CDs). Furthermore, molecular-dynamics calculations revealed that the aggregation properties of CD derivatives significantly influence their complexation behavior. Our docking calculations showed that RAMEB (random methylated beta-CD) is the beta-CD derivative that possesses the lowest tendency to aggregate. Solubility experiments yielded the same results, namely, RAMEB complexes possess the best water solubility. Our results showed that complexation of a ligand not buried inside of the CD cavity is dependent on two factors: i) the geometry of the inclusion part of the complex; ii) the self-aggregation property of the CD itself. The lower affinity the CDs possess for self-aggregation, the more likely are they involved in interactions with carotenoids. These results suggest that self-aggregation of CDs should be considered as an important parameter determining complexation in general.

Micrometer-sized rodlike structure formed by the secondary assembly of cyclodextrin nanotube

In this work, we report the observation on the self-assembly of β-CD nanotube induced by 2-phenyl-5-(4-diphenylyl)1,3,4-oxadiazole (PBD) molecule with fluorescence microscopy and transmission electron microscopy (TEM). Micrometer-sized rodlike structure is formed by the secondary assembly of cyclodextrin nanotube driven by the inter-nanotubular hydrogen bonding. The effects of pH value, urea, DMF and NaCl on the formation of the rodlike structure are investigated. Dynamic light scattering (DLS) is applied to further characterize the formation of the PBD– β-CD nanotube. The effect of light scattering on the measurement of fluorescence anisotropy of PBD in the aqueous solutions of β-CD is corrected. A new mechanism of cyclodextrin aggregation is proposed for this system.

Probing specific protein recognition by size-controlled glycosylated cyclodextrin nanoassemblies

The balance between hydrophobic and hydrophilic components in amphiphilic β-cyclodextrins, targeted by receptor specific groups (SC6CDGlc, SC6CDGal, SC16CDGlc, SC16CDGal), sensitively influences the structural properties of these systems. The different amphiphilic features of single cyclodextrins generate micellar aggregates and vesicles with an internal aqueous compartment able to encapsulate guests, such as rhodamine 6G. Small-angle light scattering (SAXS), cryo-TEM and AFM investigations describe the size and shape of these self-organized glycoligands. Recognition of the nanoassemblies by a specific receptor has effectively been demonstrated by means of time resolved fluorescence and is addressed in water by the morphological properties of cyclodextrin aggregates. Exclusively galactosylated thiohexyl-cyclodextrin binds specifically lectin from Pseudomonas aeruginosa. β-D-Galactose competes with galactosylated cyclodextrin aggregates by inhibiting lectin binding but does not affect the mesoscopic environment of the protein. The better selectivity of the less hydrophobic cyclodextrins towards lectin should probably be ascribed to the morphology (size and shape) of these cyclodextrin aggregates. The recognition properties of this particular cyclodextrin (SC6CDGal) are probably due to the presence of small micelles which interact more efficiently with the lectin binding site. The modulation of the hydrophobic–hydrophilic balance of the macrocycle labelled with targeting groups allows the design of “active” nanosized carriers for drug delivery.

The Aggregation of Cyclodextrins as Studied by Photon Correlation Spectroscopy

Photon correlation spectroscopy has been used to study theaggregation processes of natural and some modified cyclodextrins (CDs) in diluted aqueoussolutions. α-, β-, and γ-CD form large, polydisperse aggregatesin water, although the aggregation capability is different depending on the macrocycle considered. γ-CD solutions filtered through 0.2~μm give a single-modaldistribution of aggregates of 224 nm in size. The monomeric γ-CD can be isolated by filtering through 0.1 μm. α-CD displays a bimodaldistribution (monomer + aggregates) with both pore sizes. At the concentrations studied (0.012 M) the contribution in mass of the aggregates with both CDs isnegligible. β-CD is much more persistent in its aggregation, even after sievingits solutions through 0.02 μm filters, and time dependent. The aggregation displayed byCDs with partial substitution of the OH groups (Methyl-β-CD and Hydroxypropyl-β-CD) is much weaker, indicating the implication of the hydrophilic rims ofthe CDs in the process. High temperatures, addition of urea or electrolytes andionisation of the OH groups by raising the pH, prevent the aggregation.