Antifungal Activity of Econazole Nitrate/Cyclodextrin Complex: Effect of pH 2 and Formation of Complex Aggregates

Econazole nitrate (ECN) is a weakly basic drug with very low aqueous solubility that hampers its permeation through biological membranes and results in low ECN bioavailability. Formation of drug/cyclodextrin (drug/CD) inclusion complexes is a formulation technology that can be applied to enhance drug solubility in aqueous media. The aim of this study was to determine the effect of CD complexation and pH adjustments on the ECN solubility. The ECN pHsolubility and ECN/CD phase-solubility profiles were determined. The solubility of ECN in aqueous acidic solutions containing α-cyclodextrin (αCD) was relatively high and much higher than in aqueous γ-cyclodextrin (γCD) solutions under same conditions. The complexation efficiency of the ECN/CD complex was relatively low for the unionized drug. Formation of ECN/CD inclusion complex was verified by proton nuclear magnetic resonance spectroscopy. Formation of ECN/CD complexes enhanced the drug stability during autoclaving. γCD complexes self-assembled to form nanoand microparticles whereas αCD complexes had negligible tendency to selfassemble. Formation of CD complex nano- and microparticles was investigated by dynamic light scattering and by drug permeation through semipermeable membranes of different molecular weight cut-off. The largest aggregate fraction was observed for the unionized ECN in aqueous pH 7.5 solution containing high CD concentration, that is 10% (w/v) CD. It was shown that in acidic solutions ECN/αCD can enhance the antifungal activity to filamentous fungi. This was associated with the increased ECN solubility and increase of readily available ECN molecules in aqueous αCD solutions.This work was financially supported by European Union grant No. MSCA-ITN-2017-765441 (transMed), Thailand Research Fund grant No. RSA5980050 and Faculty of Pharmaceutical Sciences, University of Iceland.Peer-reviewed (accepted version

Solubility of Cyclodextrins and Drug/Cyclodextrin Complexes

Publisher's version (útgefin grein)Cyclodextrins (CDs), a group of oligosaccharides formed by glucose units bound together in a ring, show a promising ability to form complexes with drug molecules and improve their physicochemical properties without molecular modifications. The stoichiometry of drug/CD complexes is most frequently 1:1. However, natural CDs have a tendency to self-assemble and form aggregates in aqueous media. CD aggregation can limit their solubility. Through derivative formation, it is possible to enhance their solubility and complexation capacity, but this depends on the type of substituent and degree of substitution. Formation of water-soluble drug/CD complexes can increase drug permeation through biological membranes. To maximize drug permeation the amount of added CD into pharmaceutical preparation has to be optimized. However, solubility of CDs, especially that of natural CDs, is affected by the complex formation. The presence of pharmaceutical excipients, such as water-soluble polymers, preservatives, and surfactants, can influence the solubilizing abilities of CDs, but this depends on the excipients’ physicochemical properties. The competitive CD complexation of drugs and excipients has to be considered during formulation studies.Peer Reviewe

Solubility of Cyclodextrins and Drug/Cyclodextrin Complexes

Publisher's version (útgefin grein)Cyclodextrins (CDs), a group of oligosaccharides formed by glucose units bound together in a ring, show a promising ability to form complexes with drug molecules and improve their physicochemical properties without molecular modifications. The stoichiometry of drug/CD complexes is most frequently 1:1. However, natural CDs have a tendency to self-assemble and form aggregates in aqueous media. CD aggregation can limit their solubility. Through derivative formation, it is possible to enhance their solubility and complexation capacity, but this depends on the type of substituent and degree of substitution. Formation of water-soluble drug/CD complexes can increase drug permeation through biological membranes. To maximize drug permeation the amount of added CD into pharmaceutical preparation has to be optimized. However, solubility of CDs, especially that of natural CDs, is affected by the complex formation. The presence of pharmaceutical excipients, such as water-soluble polymers, preservatives, and surfactants, can influence the solubilizing abilities of CDs, but this depends on the excipients’ physicochemical properties. The competitive CD complexation of drugs and excipients has to be considered during formulation studies.Peer Reviewe

Physicochemical and Stability Evaluation of Topical Niosomal Encapsulating Fosinopril/γ-Cyclodextrin Complex for Ocular Delivery

Funding Information: Funding: This work was financially supported by the European Union’s Eurostar Program under project No. PREVIN E11008 and by The Second Century Fund (C2F), Chulalongkorn University. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.This study aimed to develop a chemically stable niosomal eye drop containing fosinopril (FOS) for lowering intraocular pressure. The effects of cyclodextrin (CD), surfactant types and membrane stabilizer/charged inducers on physiochemical and chemical properties of niosome were evaluated. The pH value, average particle size, size distribution and zeta potentials were within the acceptable range. All niosomal formulations were shown to be slightly hypertonic with low viscosity. Span® 60/dicetyl phosphate niosomes in the presence and absence of γCD were selected as the optimum formulations according to their high %entrapment efficiency and negative zeta potential values as well as controlled release profile. According to ex vivo permeation study, the obtained lowest flux and apparent permeability coefficient values confirmed that FOS/γCD complex was encapsulated within the inner aqueous core of niosome and could be able to protect FOS from its hydrolytic degradation. The in vitro cytotoxicity revealed that niosome entrapped FOS or FOS/γCD formulations were moderate irritation to the eyes. Furthermore, FOS-loaded niosomal preparations exhibited good physical and chemical stabilities especially of those in the presence of γCD, for at least three months under the storage condition of 2–8 °C.Peer reviewe

Gertie Lamont standing holding spade, Clermont, Queensland, ca. 1920 [picture] /

Condition: Emulsion lift, scratched, dirty.; Accompanied by photographic print.; Gertie was Mrs Gordon Pullar's youngest sister; taken at Pullar home in Lime Street.; Glass negative no. 207.; Part of the Gordon Cumming Pullar collection of glass negatives of Clermont, Yeppoon and nearby locations, Queensland, ca. 1905-1932.; Photograph no. 34 in the book A shifting town : glass-plate images of Clermont and its people.; Also available in an electronic version via the internet at: http://nla.gov.au/nla.pic-vn4191944; Published in: A shifting town : glass-plate images of Clermont and its people / by G.C. Pullar ; compiled by Richard and Marguerite Stringer ; text by Marguerite Stringer. St. Lucia, Qld. : University of Queensland Press, 1986

Wally and the Major [picture] : aggravating /

Part of the Stan Cross Archive of cartoons and drawings, 1912-1974.; Inscription: "Wally and the Major appear daily in The Sun"-- Lower right. "335"--In pencil, upper right corner; "5-1"--In pencil, lower right.; Also available in an electronic version via the internet at: http://nla.gov.au/nla.pic-vn4301465

Effect of γ-cyclodextrin on solubilization and complexation of irbesartan: influence of pH and excipients.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageIn effort to prepare an eye drop formulation of irbesartan, the effect of γ-cyclodextrin complexation on irbesartan solubilization in aqueous solutions was investigated. The optimum cyclodextrin concentration for formation of irbesartan/cyclodextrin inclusion complex was found to be 10% (w/v) and the solubility of ionized irbesartan/γ-cyclodextrin complex (at pH 7.2) was shown to be three fold greater than that of the unionized complex (at pH 4.3). The irbesartan flux through semipermeable membranes increased with increasing γ-cyclodextrin concentration at both pH values. However, the ionized complex displayed decrease in the drug permeation coefficient with increasing cyclodextrin concentration. The effect of four pharmaceutical excipients on the cyclodextrin solubilization was investigated. EDTA, hydroxypropyl methylcellulose, and tyloxapol increased complexation efficiency of γ-cyclodextrin while benzalkonium chloride had negligible effect. The largest solubilization was observed in the eye drop vehicle that contained all four excipients in addition to γ-cyclodextrin. Dynamic light scattering measurements disclosed that excipients had impact on size of complex aggregates and consequently on the drug flux through the semipermeable membranes. Complex of irbesartan/γ-cyclodextrin was characterized by FT-IR, (1)H NMR, XRPD, and TEM techniques.Icelandic Center of Research, (RANNÍS), University of Icelan

Cyclodextrin-based formulation of carbonic anhydrase inhibitors for ocular delivery - A review.

To access publisher's full text version of this article click on the hyperlink belowCarbonic anhydrase inhibitors (CAIs) are used as systemic and topical agents for lowering intraocular pressure (IOP) in patients with glaucoma. Owing to the wide distribution of CAs and their physiological functions in various tissues, systemic administration of CAIs may lead to unwanted side effects. Thus, exploration of drugs targeting the specific CA isoenzyme in ocular tissues and application of the same as topical eye drops would be desirable. However, the anatomical and physiological barriers of the eyes can limit drug availability at the site. The very low aqueous solubility of CAI agents can further hamper drug bioavailability, consequently resulting in insufficient therapeutic efficacy. Solubilization of drugs using cyclodextrin (CD) complexes can enhance both solubility and permeability of the drugs. The use of CD for such purposes and development and testing of topical CAI eye drops containing CD have been discussed in detail. Further, pharmaceutical nanotechnology platforms were discussed in terms of investigation of their IOP-lowering efficacies. Future prospects in drug discovery and the use of CD nanoparticles and CD-based nanocarriers to develop potential topical CAI formulations have also been described here. Keywords: Carbonic anhydrase inhibitor; Cyclodextrin; Glaucoma; Intraocular pressure; Nanocarrier; Solubilization

yCD/HPyCD mixtures as solubilizer: solid-state characterization and sample dexamethasone eye drop suspension.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldPURPOSE: Study the complexation of dexamethasone in combinations of γ-cyclodextrin (γCD) and 2-hydroxypropyl-γ-cyclodextrin (HPγCD) with emphasis on solid characterization and development of aqueous dexamethasone eye drop suspension for drug delivery through sclera. METHODS: Dexamethasone/cyclodextrin (dexamethasone/CD) solid complex systems were prepared and characterized by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and by in vitro drug dissolution testing. Sample eye drop suspensions were prepared applying solubilizer/suspender consisting of γCD/HPγCD mixtures, poloxamer 407 (P407) and polyvinylpyrrolidone. The eye drop suspension was characterized by its physicochemical properties. RESULTS: The solid characterization techniques applied suggested that solid complexes were being formed. The results indicated that dexamethasone formed non-inclusion or micelle-like aggregates with HPγCD and the γCD/HPγCD mixture. The dissolution and dexamethasone release from the solid dexamethasone/γCD/HPγCD complexes was much faster than from the solid dexamethasone/γCD and dexamethasone/HPγCD complexes. The diameter of the solid particles in the dexamethasone eye drop suspension formulations were in all cases less than 10 μm with a mean diameter from 2.5 to 5.8 μm. The particle size decreased with increasing amount of P407. Permeation studies through semipermeable membrane and porcine sclera showed that increasing the amount HPγCD could enhance drug transport through the membrane barriers and this was related to enhanced drug solubility. The permeation rates were, however, decreased compared to formulation containing γCD alone due to larger hydrodynamic diameter of dexamethasone/γCD/HPγCD complex aggregates. All formulations were both chemically stable for at least 8 months at 25°C and 40°C. CONCLUSIONS: Combination of γCD and HPγCD, i.e., formation of dexamethasone/γCD/HPγCD complexes, resulted in synergistic effect. That is the mixture had greater solubilizing effect than the individual CD, resulted in enhanced dissolution and drug delivery through membranes. Furthermore, it is possible to control the drug release rate by adjusting the γCD:HPγCD ratio in the solid dexamethasone/γCD/HPγCD complexes