Cyclodextrin–poloxamer aggregates as nanocarriers in eye drop formulations: dexamethasone and amphotericin B

In this present study cyclodextrin (CD)–poloxamer aggregates were characterized and developed as ophthalmic drug carriers. The combined effect of γCD/2-hydroxypropyl-γCD (HPγCD) mixtures and poloxamer on solubilization and permeability of two model drugs, dexamethasone (Dex) and amphotericin B (AmB), was investigated. The CD–poloxamer interaction and complex aggregation were examined by ¹H nuclear magnetic resonance (¹H-NMR), their solubilizing ability by high-performance liquid chromatography, and their particle size determined by dynamic light scattering and transmission electron microscopy. Formulations containing either 1.5% w/v Dex or 0.15% w/v AmB in eye drop suspensions containing various γCD/HPγCD ratios and poloxamer 407 (P407) were prepared. The solubility of the drugs, surface tension and hemolytic effect of the eye drops and drug permeation from selected formulations were determined. The ¹H-NMR study showed that P407 formed inclusion complex with CDs by inserting its poly(propylene oxide) segment into the CD cavity. P407 and γCD interacted with each other to form nanosized aggregates, and the observed concentration of dissolved γCD and P407 progressively decreased with increasing γCD and P407 concentrations. Including a high proportion of HPγCD improved the drug solubilization and reduced the hemolytic effect. The surface tension of the formulations decreased with increasing P407 concentration. Furthermore, increasing P407 content in the formulations enhanced formation of complex aggregates with consequent slower drug release. It was concluded that the drug/γCD/HPγCD complex was stabilized by P407 through formation of multi-component aggregates. Thus, CD–poloxamer aggregates are self-assembled nanocarriers from which drug delivery characteristics can be adjusted by changing the γCD/HPγCD/P407 ratios.     

The Influence of Water-soluble Polymers and pH on Hydroxypropyl-β-Cyclodextrin Complexation of Drugs

The effect of water-soluble polymers and ionization of the drug molecules on the cyclodextrin, mainly 2-hydroxypropyl-β-cyclodextrin (HPβCD), solubilization of drugs was investigated. HPβCD has significant solubilizing effect on acetazolamide, prazepam, and sulfamethoxazole in aqueous solutions. All three polymers tested-i.e., hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and carboxymethylcellulose-increase the solubilizing effect of HPβCD. The polymers increase the solubilization by increasing the apparent stability constant (K_c of the drug-HPβCD complex. Thus, addition of 0.10% (w/v) HPMC to the aqueous complexation medium results in a 56% increase in K, for the acetazolamide-HPβCD complex and a 200% increase in K_c for the prazepam-HPβCD complex. Addition of 0.25% (w/v) PVP to the complexation medium results in a 138% increase in K for the sulfamethoxazole-HPβCD complex. The HPβCD solubilization of the drugs can also be improved by ionization of the drug molecule through pH adjustments. However, larger improvements of the HPβCD solubilization are obtained when both methods are used simultaneously compared to when either method is used separately.     

Dermal delivery of ETH-615, a zwitterionic drug

ETH-615 is an amphoteric drug that forms a water-insoluble zwitterion at intermediate pH values. Increasing the aqueous solubility of ETH-615 through cyclodextrin complexation did not enhance transdermal delivery of the drug from saturated aqueous solutions. However, increasing the lipophilicity of the drug through masking of the anionic group with a pro-moiety increased the dermal and transdermal delivery of the drug. Furthermore, masking the anionic group enhanced the chemical stability of the drug, resulting in significant improvement of the shelf life of the drug in both aqueous and nonaqueous solutions.     

Effect of various marine lipids on transdermal drug delivery--in vitro evaluation

The effects of several marine lipids on the penetration of hydrocortisone and nitroglycerin through excised hairless mouse skin have been studied. Fatty acid extracts obtained by hydrolysis of Portuguese dog-fish-liver-oil or by hydrolysis of cod-liver-oil were shown to be effective skin penetration enhancers. Phospholipid obtained from squid was also shown to be effective enhancer. However, the enhancing effect of the marine products could generally be associated with their content of free unsaturated fatty acids. The fatty acid extract obtained from cod-liver-oil caused insignificant skin irritation when incorporated into an ointment base and applied to human skin.     

Co-administration of a water-soluble polymer increases the usefulness of cyclodextrins in solid oral dosage forms

PURPOSE: The aim of this study was to investigate the effect of cyclodextrins (beta-CD, HP-beta-CD and (SBE)7m-beta-CD), and co-administration of a water-soluble polymer (HPMC) and cyclodextrins, on the oral bioavailability of glibenclamide in dogs. METHODS: Effects of cyclodextrins on the aqueous solubility of glibenclamide, with and without hydroxypropylmethylcellulose (HPMC), were determined by a phase-solubility method. Solid inclusion complexes were prepared by freeze-drying. Glibenclamide was administered orally and intravenously to beagle dogs. RESULTS: Aqueous solubility of glibenclamide increased as a function of cyclodextrin concentration, showing an AL-type diagram for beta-CD and an Ap-type diagrams for both of the beta-CD derivatives studied. HPMC enhanced the solubilising effect of cyclodextrins, but did not affect the type of phase-solubility diagram. Orally administered glibenclamide and its physical mixture with HP-beta-CD showed poor absolute bioavailability, while orally administered glibenclamide/cyclodextrin-complexes significantly enhanced the absolute bioavailability of glibenclamide. Orally administered glibenclamide/beta-CD/HPMC and glibenclamide/(SBE)7m-beta-CD/HPMC complexes showed similar absolute bioavailability compared to formulations not containing HPMC, even though 80% (in the case of (SBE)7m-beta-CD) or 40% (in the case of beta-CD) less cyclodextrin was used. CONCLUSIONS: The oral bioavailability of glibenclamide was significantly increased by cyclodextrin complexation. HPMC increased the solubilising effect of cyclodextrins and, therefore, the amount of cyclodextrin needed in the solid dosage form was significantly reduced by their co-administration. In conclusion, the pharmaceutical usefulness of cyclodextrins in oral administration may be substantially improved by co-administration of a water-soluble polymer.     

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-β-cyclodextrin (HPβCD). 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 (K_c) 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.     

Tagging Icelandic text: an experiment with integrations and combinations of taggers

We use integrations and combinations of taggers to improve the tagging accuracy of Icelandic text. The accuracy of the best performing integrated tagger, which consists of our linguistic rule-based tagger for initial disambiguation and a trigram tagger for full disambiguation, is 91.80%. Combining five different taggers, using simple voting, results in 93.34% accuracy. By adding two linguistically motivated rules to the combined tagger, we obtain an accuracy of 93.48%. This method reduces the error rate by 20.5%, with respect to the best performing tagger in the combination pool.     

Effect of Cyclodextrins on Topical Drug Delivery to the Eye

Cyclodextrins are oligosaccharides which form a new group of pharmaceutical excipients. Cyclodextrins have been added to aqueous eye drop preparations to solubilize lipophilic water-insoluble drug, to increase the chemical stability of drugs, or to reduce local drug irritation in the eye. Hydrophilic cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin, have been shown to be nontoxic to the eye and are generally well tolerated in aqueous eye drop formulations. However, improper formulation of aqueous cyclodextrin containing eye drop solutions can reduce the topical availability of the drug molecule. This paper reviews the effects of cyclodextrins and aqueous cyclodextrin eye drop formulations on the ocular bioavailability of drugs.     

Preparation, characterization, and anesthetic properties of 2-hydroxypropyl-beta-cyclodextrin complexes of pregnanolone and pregnenolone in rat and mouse

Prototype formulations of the progesterone derivatives pregnanolone and pregnenolone were prepared by solubilizing the steroids in 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). The aqueous solubility of the steroids was increased as a function of HP beta CD concentration generating linear (AL) or curvilinear (AP) phase-solubility profiles. While the solubility of pregnanolone could not be increased with the addition of water-soluble pharmaceutical polymers, the concentration of pregnenolone in HP beta CD was increased more than 60% by the addition of small amounts (0.10%) of (hydroxypropyl)methylcellulose. Mice studies found that while pregnanolone was highly potent in an HP beta CD vehicle, pregnenolone was devoid of activity. Since pregnenolone and pregnanolone differ marginally in structure and physicochemical profile, the data suggest that these derivatives interact via a specific receptor and not via nonspecific membrane perturbations. Sex differences in the action of the pregnanolone complex was observed in that parenteral (i.v. and i.p.) drug administration was more effective in males than females. These data are in contrast to observations made in the case of alfaxalone, a related steroid anesthetic, in which the sex difference favored female animals. On the other hand, females appeared to be more sensitive to the effects of the pregnanolone complex when administered orally. Finally, parenteral pregnanolone was more toxic to males than females with LD50 (i.v.) values of 355 and 548 micromol/kg, respectively.     

Interactions between preservatives and 2-hydroxypropyl-β-cyclodextrin

The interactions between several commonly used preservatives, i.e. benzalkonium chloride, chlorhexidine gluconate, chlorobutanol, methylparaben and propylparaben, and 2-hydroxypropyl-β-cyclodextrin were investigated. The interactions were shown to be twofold. Firstly, the preservative molecules can displace the drug molecules from the cyclodextrin cavity, thus, reducing the solubilizing effects of the cyclodextrin. Secondly, the antimicrobial activity of the preservatives were reduced by formation of preservative-cyclodextrin inclusion complexes. The magnitude of the interactions were dependent on the degree of complexation.